Controlled non-classified filling device and method

ABSTRACT

An injection member penetrates an elastic septum of a device defining a sealed, empty, sterile chamber in fluid communication with the septum. During penetrating, an annular interface is formed between the septum and the injection member extending axially between a penetration point on an interior surface of the septum in fluid communication with the sterile chamber, and an exterior surface of the septum engaging the injection member. The injection member is de-contaminated by (i) friction between the septum and injection member at the annular interface, and (ii) elongation of the septum at the annular interface. A substance is introduced through the injection member and into the sterile chamber of the device, the injection member is then withdrawn from the septum, the septum reseals itself at the resulting penetration aperture, and the chamber is maintained sterile throughout the foregoing steps.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application claims benefit under 35 U.S.C. §119 tosimilarly-titled U.S. Provisional Patent Application No. 61/798,210,filed Mar. 15, 2013, which is hereby incorporated by reference in itsentirety as part of the present disclosure.

FIELD OF THE INVENTION

The present invention relates to devices and methods for sterile oraseptic filling of substances, such as liquids, gels, creams, gases orpowders, into devices or containers, and more specifically, to suchdevices and methods that sterile or aseptic fill closed containers anddevices.

BACKGROUND OF THE INVENTION

A cleanroom is an environment, typically used in manufacturing orscientific research, that has a low level of environmental pollutantssuch as dust, airborne microbes, aerosol particles and chemical vapors.A cleanroom has a controlled level of contamination that is specified bythe number of particles per cubic meter at a specified particle size. Togive perspective, the ambient air outside in a typical urban environmentcontains 35,000,000 particles per cubic meter in the size range 0.5 μmand larger in diameter, corresponding to an ISO 9 cleanroom, while anISO 1 cleanroom allows no particles in that size range and only 12particles per cubic meter of 0.3 μm and smaller.

Cleanrooms can be very large. Entire manufacturing facilities can becontained within a cleanroom with factory floors covering thousands ofsquare meters. They are used extensively in semiconductor manufacturing,biotechnology, the life sciences and other fields that are verysensitive to environmental contamination.

The air entering a cleanroom from outside is filtered to exclude dust,and the air inside is constantly recirculated through high-efficiencyparticulate air (HEPA) and/or ultra-low penetration air (ULPA) filtersto remove internally generated contaminants. Staff enter and leavethrough airlocks (sometimes including an air shower stage), and wearprotective clothing such as hoods, face masks, gloves, boots andcoveralls. Equipment inside the cleanroom is designed to generateminimal air contamination. Only special mops and buckets are used.Cleanroom furniture is designed to produce a minimum of particles and tobe easy to clean. Common materials such as paper, pencils, and fabricsmade from natural fibers are often excluded, and alternatives used. Somecleanrooms are kept at a positive pressure so that if there are anyleaks, air leaks out of the chamber instead of unfiltered air coming in.Some cleanroom HVAC systems control the humidity to low levels, suchthat extra equipment is necessary (e.g., “ionizers”) to preventelectrostatic discharge (ESD) problems.

Cleanrooms maintain particulate-free air through the use of either HEPAor ULPA filters employing laminar or turbulent airflow principles.Laminar, or unidirectional, air flow systems direct filtered airdownward in a constant stream towards filters located on walls near thecleanroom floor or through raised perforated floor panels to berecirculated. Laminar airflow systems are typically employed acrossabout 80 percent of a cleanroom ceiling to maintain constant airprocessing. Stainless steel or other non-shed materials are used toconstruct laminar airflow filters and hoods to prevent excess particlesentering the air. Turbulent, or non-unidirectional, airflow uses bothlaminar airflow hoods and non-specific velocity filters to keep air in acleanroom in constant motion, although not all in the same direction.The rough air seeks to trap particles that may be in the air and drivethem towards the floor, where they enter filters and leave the cleanroomenvironment.

In the pharmaceutical industry, the term “isolator” covers a variety ofpieces of equipment. One group has the main objective of providingcontainment for the handling of dangerous materials either asepticallyor not. Another group has the main objective of providing amicrobiologically controlled environment within which aseptic operationscan be carried out. Containment isolators often employ negative internalair pressure and most isolators used for aseptic processing employpositive pressure. A sporicidal process, usually delivered by gassing,can be used to aid microbiological control. Some large-scale isolatorsprovide an opening, often called a mouse hole, to permit continuousremoval of sealed product. Other isolators remain sealed throughoutproduction operations.

Aseptic operations can include sterility testing or aseptic processingto produce medicinal products. Isolators are used to provide amicrobiologically controlled environment for aseptic processing forproducing medicinal products labeled as sterile. Isolators could be seenas a more encompassing development of the barriers used in conventionalclean rooms. The clean room barriers evolved from plastic flexiblecurtains through to rigid barriers with glove ports. The objectives ofbarriers are to increasingly separate the surrounding clean roomincluding the operator from the critical zone where aseptic operationsare carried out and sterile materials are exposed. When the degree ofcontainment is nearly complete, sporicidal procedures can be appliedwithout harming the operators. Accordingly, an isolator is anarrangement of physical barriers that are integrated to the extent thatthe isolator can be sealed in order to carry out a routine leak testbased on pressure to meet specified limits. Internally it provides aworkspace, which is separated from the surrounding environment.Manipulations can be carried out within the space from the outsidewithout compromising its integrity. Industrial isolators used foraseptic processing are isolators in which the internal space and exposedsurfaces are microbiologically controlled. Control is achieved by theuse of microbiologically retentive filters, sterilization processes,sporicidal processes (such as by gassing) and prevention ofrecontamination from the external environment. A sporicidal process is agaseous, vapor or liquid treatment applied to surfaces, using an agentthat is recognized as capable of killing bacterial and fungal spores.The process is applied to internal surfaces of the isolator and externalsurfaces of materials inside the isolator, when conventionalsterilization methods are not required.

Cleanrooms are classified according to the number and size of particlespermitted per volume of air. Large numbers like “class 100” or “class1000” refer to FED-STD-209E, and denote the number of particles of size0.5 μm or larger permitted per cubic foot of air. The standard alsoallows interpolation, so it is possible to describe, for example, “class2000”. Small numbers refer to ISO 14644-1 standards, which specify thedecimal logarithm of the number of particles 0.1 μm or larger permittedper cubic meter of air. For example, an ISO class 5 cleanroom has atmost 10⁵=100,000 particles per cubic meter. Because 1 m³ isapproximately 35 ft³, the two standards are mostly equivalent whenmeasuring 0.5 μm particles, although the testing standards differ.Ordinary room air is approximately class 1,000,000 or ISO 9. Adiscrete-particle-counting, light-scattering instrument is used todetermine the concentration of airborne particles, equal to and largerthan the specified sizes, at designated sampling locations.

US FED STD 209E Cleanroom Standards maximum particles/ft³ ISO Class ≧0.1μm ≧0.2 μm ≧0.3 μm ≧0.5 μm ≧5 μm equivalent 1 35 7.5 3 1 0.007 ISO 3 10350 75 30 10 0.07 ISO 4 100 3,500 750 300 100 0.7 ISO 5 1,000 35,0007,500 3000 1,000 7 ISO 6 10,000 350,000 75,000 30,000 10,000 70 ISO 7100,000 3.5 × 10⁶ 750,000 300,000 100,000 700 ISO 8

ISO 14644-1 Cleanroom Standards maximum particles/m³ FED STD 209E Class≧0.1 μm ≧0.2 μm ≧0.3 μm ≧0.5 μm ≧1 μm ≧5 μm equivalent ISO 1 10 2.371.02 0.35 0.083 0.0029 ISO 2 100 23.7 10.2 3.5 0.83 0.029 ISO 3 1,000237 102 35 8.3 0.29 Class 1 ISO 4 10,000 2,370 1,020 352 83 2.9 Class 10ISO 5 100,000 23,700 10,200 3,520 832 29 Class 100 ISO 6 1.0 × 10⁶237,000 102,000 35,200 8,320 293 Class 1,000 ISO 7 1.0 × 10⁷ 2.37 × 10⁶1,020,000 352,000 83,200 2,930 Class 10,000 ISO 8 1.0 × 10⁸ 2.37 × 10⁷1.02 × 10⁷ 3,520,000 832,000 29,300 Class 100,000 ISO 9 1.0 × 10⁹ 2.37 ×10⁸ 1.02 × 10⁸ 35,200,000 8,320,000 293,000 Room air

Both FS 209E and ISO 14644-1 assume log-log relationships betweenparticle size and particle concentration. For that reason, zero particleconcentration does not exist. The table locations without entries arenon-applicable combinations of particle sizes and cleanliness classes,and should not be read as zero.

BS 5295 Cleanroom Standards maximum particles/m³ Class ≧0.5 μm ≧1 μm ≧5μm ≧10 μm ≧25 μm Class 1 3,000 0 0 0 Class 2 300,000 2,000 30 Class 31,000,000 20,000 4,000 300 Class 4 200,000 40,000 4,000

BS 5295 Class 1 also requires that the greatest particle present in anysample does not exceed 5 μm.

GMP EU Classification maximum particles/m³ At Rest At Rest In OperationIn Operation Class 0.5 μm 5 μm 0.5 μm 5 μm Class A 3,520 20 3,500 20Class B 3,520 29 352,000 2,900 Class C 352,000 2,900 3,520,000 29,000Class D 3,520,000 29,000 n/a n/a

The term “sterility assurance level” (SAL) is used in microbiology todescribe the probability of a single unit being non-sterile after it hasbeen subjected to a sterilization process. For example, medical devicemanufacturers design their sterilization processes for an extremely lowSAL—“one in a million” devices should be nonsterile. SAL is also used todescribe the killing efficacy of a sterilization process, where a veryeffective sterilization process has a very low SAL.

In microbiology, it is considered impossible to prove that all organismshave been destroyed because: 1) they could be present but undetectablesimply because they are not being incubated in their preferredenvironment, and 2) they could be present but undetectable because theirexistence has never been discovered. Therefore, SALs are used todescribe the probability that a given sterilization process has notdestroyed all of the microorganisms.

Mathematically, SALs referring to probability are usually very smallnumbers and so are properly expressed as negative exponents (e.g., “TheSAL of this process is 10 to the minus six”). SALs referring tosterilization efficacy are usually much larger numbers and so areproperly expressed as positive exponents (e.g., “The SAL of this processis 10 to the six”). In this usage, the negative effect of the process issometimes inferred by using the word “reduction” (e.g., “This processgives a six-log reduction”).

SALs can be used to describe the microbial population that was destroyedby a sterilization process. Each log reduction (10⁻¹) represents a 90%reduction in microbial population. So a process shown to achieve a“6-log reduction” (10⁻⁶) will reduce a population from a millionorganisms (10⁶) to very close to zero.

In order to sterile or aseptically fill substances into containers ordevices, such as pharmaceuticals, vaccines, and food products,cleanrooms and isolators have been employed in order to ensure therequisite SALs to maintain the filled product aseptic or sterile.However, as summarized above, cleanrooms and isolators can requiresubstantial capital expenditures, operational costs, numerous controls,sophisticated and expensive facilities, and/or highly trained personnel.Accordingly, it would be desirable to sterile or aseptically fillsubstances without such cleanrooms and/or isolators, while neverthelessensuring the requisite SALs to maintain the filled substances aseptic orsterile.

It is therefore an object of the present invention to overcome one ormore of the above-described drawbacks and/or disadvantages of the priorart.

SUMMARY OF THE INVENTION

In accordance with one aspect, a method comprises the following steps:

-   -   (a) penetrating an elastic septum of a device with an injection        member, wherein the device defines a sealed, empty, sterile        chamber in fluid communication with the elastic septum;    -   (b) during the penetrating step, forming an annular interface        between the elastic septum and the injection member extending        axially between a penetration point on an interior surface of        the elastic septum in fluid communication with the sterile        chamber, and an exterior surface of the septum engaging the        injection member, and de-contaminating the injection member by        at least one of (i) friction between the elastic septum and        injection member at the annular interface, and (ii) elongation        of the elastic septum at the annular interface;    -   (c) introducing a substance through the injection member and        into the sterile chamber of the device;    -   (d) withdrawing the injection member from the elastic septum;    -   (e) allowing the elastic septum to reseal itself at a        penetration aperture resulting from withdrawal of the injection        member; and    -   (f) maintaining the chamber sterile throughout steps (a) through        (e).

Some embodiments comprise performing the penetrating step in an ambientenvironment defining a level of contamination greater than about class100 or ISO 5. Some such embodiments comprise performing steps a) throughe) in an ambient environment defining a level of contamination greaterthan about class 100 or ISO 5. Some embodiments comprise performing thepenetrating step in an ambient environment defining a level ofcontamination greater than about class 100 or ISO 5 and less than orequal to about class 100,000 or ISO 8.

In some embodiments, the de-contaminating of the injection memberincludes achieving at least approximately a 3 log reduction inbio-burden at the annular interface between the elastic septum andinjection member. In some such embodiments, the de-contaminating of theinjection member includes achieving at least approximately a 5 logreduction in bio-burden at the annular interface between the elasticseptum and injection member. In some such embodiments, thede-contaminating of the injection member includes achieving at leastapproximately a 6 log reduction in bio-burden at the annular interfacebetween the elastic septum and injection member.

Some embodiments further comprise resealing the resulting penetrationaperture. In some such embodiments, the resealing step includesresealing the resulting penetration aperture with a mechanical seal, aliquid sealant, a thermal seal, and/or a chemical seal. Some embodimentsfurther comprise transmitting radiation onto the resulting penetrationaperture to effect or further effectuate the seal.

In some embodiments, the elastic septum includes a penetration zonedefining an approximate dome-shape, and the penetrating step includespenetrating the elastic septum in the dome-shaped penetration zone. Insome such embodiments, the elastic septum defines a substantially convexexterior surface, and a substantially concave interior surface oppositethe convex exterior surface. In some such embodiments, the interiorsurface of the septum defines a relatively recessed surface extendingsubstantially about the penetration zone. In some such embodiments, therelatively recessed surface is a groove.

In some embodiments, the elastic septum defines a penetration zone thatis penetrated by the injection member, and the penetration zone isshaped to enhance the pressure exerted by the elastic septum onto theinjection member during the penetrating step. In some such embodiments,the penetration zone of the elastic septum is approximately dome shaped.In some such embodiments, the approximately dome-shaped penetration zonedefines a substantially convex exterior surface, and a substantiallyconcave interior surface.

In some embodiments, during the penetrating step, the internal surfaceof the elastic septum forms an initial crack at substantially themaximum elongation of the elastic septum by the injection member.

In some embodiments, the annular interface is defined by a portion ofthe penetrated elastic septum extending annularly about the injectionmember substantially throughout an axial distance extending between theinterior and exterior points of contact between the penetrated septumand injection member. In some embodiments, the axial distance is atleast about ½ mm. In some embodiments, the axial distance is at leastabout 1 mm. And in some such embodiments, the axial distance is at leastabout 1⅓ mm.

In some embodiments, the annular interface between the elastic septumand injection member defines a substantially inverted, frusto-conicalshape.

In some embodiments, the coefficient of friction of the septum-engagingsurface of the injection member is less than the coefficient of frictionof the penetrated portion of the elastic septum.

Some embodiments further comprise reducing strain on an interior surfaceof the septum within a zone of penetration of the injection memberduring the penetrating step with a groove formed on an interior surfaceof the septum and extending substantially about the zone of penetration.In some such embodiments, the groove extends annularly about andadjacent or contiguous to the zone of penetration.

In some embodiments, the injection member includes at least one port fordispensing the substance from the injection member, and the methodfurther includes sealing the port with respect to the ambient atmosphereuntil at least a portion of the port is in fluid communication with thesterile chamber. Some such embodiments further comprise moving at leastone of a closure and the port of the injection member from a closedposition sealing the port with respect to ambient atmosphere to an openposition opening the port into fluid communication with the sterilechamber. Some such embodiments further comprise, before or during thewithdrawing step, moving at least one of the closure and the port of theinjection member from the open position to the closed position. Somesuch embodiments further comprise introducing the substance from theinjection member into the sterile chamber after perforating the elasticseptum, or after part of the port passes through an interior surface ofthe elastic septum and is in fluid communication with the sterilechamber. Some such embodiments further comprise substantially sealingthe port and an interior of the injection member from ambient atmospherein the closed position. In some embodiments, the sealing includesforming a substantially fluid-tight seal with a relatively soft materialat the interface of the closure and injection member. Some embodimentsfurther comprise during the penetrating and withdrawing steps,substantially preventing contact between the port and the elasticseptum. Some such embodiments further comprise interposing the closurebetween the port and the elastic septum and substantially preventingcontact between the port and the elastic septum.

In some embodiments, the elastic septum is self-closing andsubstantially prevents the ingress of fluid through the resultingpenetration aperture. Some embodiments further comprise introducing atoxic substance through the injection member and into the sterilechamber of the device, and using the closure to prevent any exposure ofthe toxic substance to the ambient atmosphere throughout the method.

In some embodiments, the de-contaminating of the injection memberincludes exerting pressure with the elastic septum onto the injectionmember at the annular interface between the elastic septum and injectionmember and, in turn, killing organisms at the interface. In some suchembodiments, the exerting pressure on the injection member includespenetrating a substantially dome or convex shaped portion of the elasticseptum.

In some embodiments, the elastic septum defines a penetration zone thatis penetrated by the injection member, and the penetration zone of theelastic septum defines a thickness prior to penetration within the rangeof about ½ to about two times an outer diameter of the injection member.In some embodiments, the elastic septum defines a penetration zoneincluding a recess defining a reduced thickness of the elastic septum,and the penetrating step includes penetrating the elastic septum at thereduced thickness of the penetration zone. In some such embodiments, thepenetration zone recess defines a substantially frusto-conical shape. Insome embodiments, the injection member includes a penetrating tipdefining a first included angle, and the penetration zone recess definesa second included angle that is substantially the same as the firstincluded angle. In other embodiments, the injection member includes apenetrating tip defining a first included angle, and the penetrationzone recess defines a second included angle that is greater than thefirst included angle.

In accordance with another aspect, a device that is sterile filled by aninjection member defining a port that is normally sealed with respect toambient atmosphere and can be opened to dispense substance from theinjection member therethrough. The device comprises a body defining asealed, empty, sterile chamber; and an elastic septum in fluidcommunication with sealed, empty, sterile chamber. The elastic septum ispenetrable by the injection member and forms an annular interfacebetween the elastic septum and the injection member extending axiallybetween (i) a penetration point on an interior surface of the elasticseptum in fluid communication with the sterile chamber, and (ii) anexterior surface of the septum engaging the injection member. Relativemovement of at least one of the injection member and elastic septumrelative to the other de-contaminates the injection member through (i)friction between the elastic septum and injection member at the annularinterface, and/or (ii) elongation of the elastic septum at the annularinterface.

In some embodiments, the relative movement of the injection member andelastic septum opens the port of the injection member into fluidcommunication with the sterile chamber to dispense substance from theinjection member into the sterile chamber. In some embodiments, therelative movement opens the port after decontaminating the injectionmember at the annular interface and at least part of the port is passedthrough the septum.

In some embodiments, the relative movement of the injection member andelastic septum de-contaminates the injection member by at leastapproximately a 3 log reduction in bio-burden at the annular interfacebetween the elastic septum and injection member. In some suchembodiments, the relative movement of the injection member and elasticseptum de-contaminates the injection member by at least approximately a5 log reduction in bio-burden at the annular interface between theelastic septum and injection member. In some such embodiments, therelative movement of the injection member and elastic septumde-contaminates the injection member by at least approximately a 6 logreduction in bio-burden at the annular interface between the elasticseptum and injection member.

The elastic member is in some embodiments re-sealable or capable ofbeing resealed at the resulting penetration aperture. In some suchembodiments, the resulting penetration aperture of the elastic member isre-sealed with at least one of a mechanical seal, a liquid sealant, athermal seal, and/or a chemical seal.

In some embodiments, the elastic septum includes a penetration zonepenetrable by the injection member and defining an approximatedome-shape. In some such embodiments, the elastic septum defines asubstantially convex exterior surface, and a substantially concaveinterior surface opposite the convex exterior surface. In some suchembodiments, the interior surface of the septum defines a relativelyrecessed surface extending substantially about the penetration zone. Insome such embodiments, the relatively recessed surface is a groove. Someembodiments further comprise means for reducing the strain on aninterior surface of the septum during penetration thereof by theinjection member. In some such embodiments, the means is a groove formedon the interior surface of the septum and extending substantially abouta zone of penetration of the septum by the injection member.

In some embodiments, the elastic septum defines a hardness within therange of about 1 to about 100 shore A. In some such embodiments, theelastic septum defines a hardness within the range of about 20 to about80 shore A.

In some embodiments, the elastic septum defines a penetration zone thatis penetrable by the injection member, and the penetration zone isshaped to enhance the pressure exerted by the elastic septum onto theinjection member during penetration thereof by the injection member. Insome such embodiments, the penetration zone of the elastic septum isapproximately dome shaped. In some embodiments, the approximatelydome-shaped penetration zone defines a substantially convex exteriorsurface, and a substantially concave interior surface.

In some embodiments, the annular interface is defined by a portion ofthe penetrated elastic septum extending annularly about the injectionmember substantially throughout an axial distance extending between theinterior and exterior points of contact between the penetrated septumand injection member. In some such embodiments, the axial distance is atleast about ½ mm. In some such embodiments, the axial distance is atleast about 1 mm. And in some such embodiments, the axial distance is atleast about 1⅓ mm.

In some embodiments, the annular interface between the elastic septumand injection member defines a substantially inverted, frusto-conicalshape. In certain embodiments, the coefficient of friction of thepenetrated portion of the elastic septum is greater than the coefficientof friction of the septum-engaging surface of the injection member.

Some embodiments further comprise means for reducing strain on aninterior surface of the septum during penetration thereof by theinjection member. In some such embodiments, the means is an annulargroove formed on the interior surface of the septum and extendingsubstantially about a zone of penetration of the injection member on theseptum. In some such embodiments, the groove extends annularly about andadjacent or contiguous to the zone of penetration.

The elastic septum is in some embodiments self-closing and substantiallyprevents the ingress of fluid through the resulting penetrationaperture. In some embodiments, the elastic septum is configured to exertpressure onto the injection member at the annular interface between theelastic septum and injection member to thereby kill organisms at theinterface. In some such embodiments, the elastic septum includes asubstantially dome or convex shaped zone of penetration that exertspressure on the injection member during penetration thereof by theinjection member.

In some embodiments, the elastic septum defines a penetration zone thatis penetrated by the injection member, and the penetration zone of theelastic septum defines a thickness prior to penetration within the rangeof about ½ to about two times an outer diameter of the injection member.

In some embodiments, the elastic septum defines a penetration zoneincluding a recess defining a reduced thickness of the elastic septumthat is penetrated by the injection member. In some such embodiments,the penetration zone recess defines a substantially frusto-conicalshape. In some embodiments, the injection member includes a penetratingtip defining a first included angle, and the penetration zone recessdefines a second included angle that is substantially the same as thefirst included angle. In other embodiments, the injection memberincludes a penetrating tip defining a first included angle, and thepenetration zone recess defines a second included angle that is greaterthan the first included angle.

In some embodiments, an apparatus for filling and resealing a containeror other device is provided. The apparatus includes a housing at leastpartially defining a processing space and a device support forreleasably holding a sealed device defining a sealed chamber for storinga substance therein, and a penetrable portion in fluid communicationwith the chamber and penetrable by a filling or injection member. Theapparatus also includes a conveyor defining a path for transporting thesupport and the device along the path and through the processing space.Within the processing space of the apparatus, the apparatus includes ade-contamination station located on the conveyor path and configured tode-contaminate at least the penetrable surface of the penetrable septum,a filling station located on the conveyor path downstream of thede-contamination station and including at least one filling or injectionmember coupled or connectible in fluid communication with a source ofsubstance to be filled into the chamber of the device. The filling orinjection member and/or the device is movable relative to the otherwithin the filling station to penetrate the penetrable septum with thefilling or injection member, introduce substance through the filling orinjection member and into the chamber, and withdraw the filling orinjection member from the septum. A resealing station is located on theconveyor path downstream of the filling station and is configured toreseal an aperture formed in the septum during the filling of thechamber of the device at the filling station. In some embodiments, a capstorage station is configured for storing a cap removed from the fillingor injection member during filling and resealing of the device.

In some embodiments, the apparatus for filling and resealing includes acap removal device configured to remove the cap from the filling orinjection member prior to filling of the device and store the cap in thecap storage station. The cap removal device is configured to retrievethe cap from the storage station after filling and resealing of thedevice, and reapply the cap to the filling or injection member, and thenremove the capped filling or injection member from the apparatus

In some embodiments, an apparatus for filling and resealing a containerincludes a housing at least partially defining a processing space, adevice support for releasably holding a sealed device defining a sealedchamber for storing a substance therein, and a penetrable portion influid communication with the chamber and penetrable by a filling orinjection member, and a conveyor defining a path for transporting thesupport and the device along the path and through the processing space.Within the processing space is a de-contamination station located on theconveyor path and configured to de-contaminate at least the penetrablesurface of the penetrable septum, and a filling station located on theconveyor path downstream of the de-contamination station and includingat least one filling or injection member coupled or connectible in fluidcommunication with a source of substance to be filled into the chamberof the device. The filling or injection member and/or the device ismovable relative to the other within the filling station to penetratethe penetrable septum with the filling or injection member, introducesubstance through the filling or injection member and into the chamber,and withdraw the filling or injection member from the septum. Aresealing station is located on the conveyor path downstream of thefilling station configured to reseal an aperture formed in the septumduring the filling of the chamber of the device at the filling station.A source of substance is placeable into and removable from fluidcommunication with the filling station by a sterile connector that isconfigured to provide a fluid flow path between the source of substanceand the filling station that is sealed from the ambient atmosphere whenthe source of substance is placed into fluid communication with thefilling station and maintains the fluid flow path sealed from theambient atmosphere when the source of substance is not in fluidcommunication with the filling station.

In some embodiments, the source of substance comprises a carousel orlike support device configured to releasable retain one or moresubstance supply containers. Further, each of the one or more substancesupply containers contains a different substance to be sterile filled,such as a respective ingredient, formula or composition, includingsubstances in liquid, semi-liquid, gel and/or powder form. In otherembodiments, the apparatus includes a control disposed between thesource of substance and the filling station configured to control theflow of substance to be filled between the source of substance and thefilling station. In some embodiments the flow path is sterile.

In other embodiments, a method is provided for filling and resealing asealed container or other device. The method includes conveying afilling or injection member into a filling device, wherein the fillingor injection member is housed within a cap. The filling device includesa housing at least partially defining a processing space, a devicesupport for releasably holding a sealed device defining a sealed chamberfor storing a substance therein, and a penetrable portion in fluidcommunication with the chamber and penetrable by a filling or injectionmember, a conveyor defining a path for transporting the support and thedevice along the path and through the processing space. Within theprocessing space, a de-contamination station is located on the conveyorpath and configured to de-contaminate at least the penetrable surface ofthe penetrable septum, and a filling station is located on the conveyorpath downstream of the de-contamination station and includes at leastone filling or injection member coupled or connectible in fluidcommunication with a source of substance to be filled into the chamberof the device. The filling or injection member and/or the device ismovable relative to the other within the filling station to penetratethe penetrable septum with the filling or injection member, introducesubstance through the filling or injection member and into the chamber,and withdraw the filling or injection member from the septum. Aresealing station is located on the conveyor path downstream of thefilling station and is configured to reseal an aperture formed in theseptum during the filling of the chamber of the device at the fillingstation. The method further includes removing the filling or injectionmember from the cap and fluidly connecting the filling or injectionmember to a source of substance, storing the cap of the filling orinjection member in the filling device at a storage position,de-contaminating at least a penetrable surface of a device including aneedle penetrable portion or septum penetrable by a filling or injectionmember and a sealed chamber in fluid communication with the penetrableseptum, moving the filling or injection member and/or the devicerelative to the other to penetrate the penetrable septum with thefilling or injection member, introducing substance through the fillingor injection member and into the chamber, and withdrawing the filling orinjection member from the septum, and sealing the penetrated region ofthe septum.

In other embodiments, the method includes the steps of retrieving thecap from the storage position and re-attaching the cap to the filling orinjection member.

One advantage of certain embodiments is that the annular interfacedecontaminates the injection member by at least one, and in someembodiments both, of (i) friction between the elastic septum andinjection member at the annular interface, and (ii) elongation of theelastic septum at the annular interface, and therefore there is no needto sterilize or otherwise decontaminate the injection member priorfilling, or to sterilize or otherwise decontaminate the ambientenvironment in which the filling occurs. Yet another advantage ofcertain embodiments is that the injection member is sealed with respectto the ambient atmosphere until it penetrates the elastic septum and thede-contaminated portion of the injection member is in fluidcommunication with the sterile chamber of the device. This furtherobviates the need to fill within a de-contaminated or controlledenvironment. Accordingly, the filling can be performed in an ambientenvironment defining a level of contamination greater than about class100 or ISO 5, such as an ambient environment defining a level ofcontamination greater than about class 100 or ISO 5 and less than orequal to about class 100,000 or ISO 8. Such a controlled, non-classifiedambient environment can obviate the substantial capital expenditures,operational costs, numerous controls, sophisticated and expensivefacilities, and/or highly trained personnel, required by the prior artas described above.

Yet another advantage is that the de-contaminating of the injectionmember can achieve at least approximately a 3 log reduction inbio-burden at the annular interface between the elastic septum andinjection member, in some embodiments at least approximately a 5 logreduction in bio-burden at the annular interface between the elasticseptum and injection member, and in further embodiments at leastapproximately a 6 log reduction in bio-burden at the annular interfacebetween the elastic septum and injection member. Accordingly, thefeatures of some embodiments can ensure significant levels of sterilityassurance without many of the drawbacks and disadvantages of the priorart.

Other objects and advantages of the present invention, and/or ofembodiments thereof, will become more readily apparent in view of thefollowing detailed description and accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a side perspective view of a device in the form of a vial;

FIG. 2 is a top perspective view of the vial of FIG. 1, with a secondclosure in the first, non-sealing position;

FIG. 3 is a partial, side cross-sectional side view of the vial of FIG.1, with the second closure in the first, non-sealing position;

FIG. 4 is a side cross-sectional view of the vial of FIG. 1, with thesecond closure in the second, sealing position;

FIG. 5 is an upper perspective view of the first and second closures ofthe vial of FIG. 1, with the second closure in the first, non-sealingposition;

FIG. 6 is a side perspective view of a filling device engageable withthe vial of FIG. 1 to aseptically or sterile fill a substance therein;

FIG. 7A is a side cross-sectional view of the filling device of FIG. 6,with the closure in the first or closed position, sealing the ports ofthe filling member from the ambient atmosphere;

FIG. 7B is a side cross-sectional view of the filling device of FIG. 6,with the closure in the second or open position, opening the ports ofthe filling member;

FIG. 8A is a partial, side cross-sectional view of the closure and tipof the filling device of FIG. 6 prior to engagement with the septum ofthe vial of FIG. 1, with the closure in the first or closed positionsealing the ports from ambient atmosphere;

FIG. 8B is a side cross-sectional view of the filling device of FIG. 6upon penetration of the tip of the filling or injection member throughthe septum of the type shown in FIG. 1, with the closure still in thefirst or closed position sealing the ports from contact with thepenetrated septum;

FIG. 8C is a side cross-sectional view of the filling device of FIG. 6wherein the tip of the filling member is penetrated through the septum,the closure is prevented from further movement through the septum, andthe filling member is allowed to continue to move into the chamberrelative to the fixed closure to expose the fluid ports to the chamberand allow the aseptic or sterile flow of substance through the openports and into the aseptic or sterile chamber;

FIG. 9A is a side cross-sectional view of another embodiment of thedistal end of the filling device of FIG. 6, including a seal over-moldedto the stop surface formed at the tip of the filling member tofacilitate forming a substantially fluid-tight or hermetic seal betweenthe closure and filling device;

FIG. 9B is a side cross-sectional view of another embodiment of thedistal end of the filling device of FIG. 6, including a seal over-moldedto the distal end of the closure to facilitate forming a substantiallyfluid-tight or hermetic seal between the closure and filling device.

FIG. 10A is a top perspective view of a device in the form of a vial,with the second closure in the first, non-sealing position;

FIG. 10B is a top perspective view the device of FIG. 10A with thesecond closure in the first, non-sealing position with a filling memberpositioned to pierce the first closure;

FIG. 10C is a side view of the device of FIG. 10A that has been filled,with the second closure in the second, sealing position;

FIG. 10D is a side view of the filled device of FIG. 10C with a needlepiercing the second closure into the chamber to permit withdrawal ofsubstance from the chamber;

FIG. 10E is a side view of the device of FIG. 10C with all of thesubstance withdrawn from the chamber;

FIGS. 11A-11D sequentially show the assembly of the device of FIG. 10A,in which the septa are over-molded onto the molded cap and the firstclosure is sealingly closed in place on the vial;

FIG. 12 is a partial, side cross-sectional side view of the device ofFIG. 10A, with the first closure in the closed position;

FIG. 13 is a top perspective view of the device of FIG. 10A with thesecond closure in the first, non-sealing position, and the device isready for filing;

FIG. 14 is a side view of the device of FIG. 13 that has been filled,with the second closure in the second, sealing position, and the hole inthe first closure formed by a filing member sealingly enclosed by thesecond closure;

FIG. 15A is a cross-sectional view of the device and filling membershown in FIG. 10B;

FIG. 15B is a cross-sectional view of the device of FIG. 10A with thetip of the filling member penetrating the septum of the first closureinto the chamber and the closure of the filling member in the first orclosed position, sealing the ports of the filling member from theambient atmosphere;

FIG. 15C is a cross-sectional view of the device of FIG. 10A with thefilling member further penetrating into the chamber with the closure ofthe filling member in the second or open position, opening the ports ofthe filling member;

FIG. 15D is a cross-sectional view of the device of FIG. 10A with thefilling member partially withdrawn from the chamber and the closure ofthe filling member moved back to the first or closed position,re-sealing the ports of the filling member from the ambient atmosphere;

FIG. 16A is a cross-sectional view of the device of FIG. 10A after thefilling member has pierced the vial septum and been withdrawn leaving ahole in the vial septum, with the second closure in the first,non-sealing position, and schematically showing sterilization of thefirst and second closures;

FIG. 16B is a cross-section view of the device of FIG. 16A with thesecond closure in the second, sealing position, enclosing the hole inthe vial septum;

FIG. 17A is a side view of the filled device of FIG. 10A ready forsampling of substance in the chamber;

FIG. 17B is a side view of the filled device of FIG. 17A with a needlepiercing the second closure into the chamber to permit sampling ofsubstance from the chamber;

FIG. 18A is a photograph of the penetration tip of the injection memberof the filling device during penetration of the elastic septum andillustrating the annular interface between the elastic septum and theinjection member extending axially between a penetration point on aninterior surface of the elastic septum in fluid communication with thesterile chamber, and an exterior surface of the septum engaging theinjection member, and de-contaminating the injection member by frictionbetween the elastic septum and injection member at the annularinterface, and elongation of the elastic septum at the annularinterface;

FIG. 18B is a partial, magnified view of FIG. 18A showing the annularinterface in further detail;

FIG. 19 is a cross-sectional view of another elastic septum including av-shaped recess defining a reduced-thickness penetration zone, and agroove on the underside of the septum extending substantially annularlyabout and adjacent to the penetration zone;

FIG. 20 is a front perspective view of an apparatus for filling andresealing sealed containers;

FIG. 21 is a front elevational view of the apparatus of FIG. 20;

FIG. 22 is a top plan view of the apparatus of FIG. 20, with a partialcut-out showing internal components;

FIG. 23 is a right-side elevational view of the apparatus of FIG. 20,with a partial cut-out showing internal components;

FIG. 24 is perspective view of another embodiment of an apparatus forfilling and resealing sealed containers;

FIG. 25 is perspective view of another embodiment of an apparatus forfilling and resealing sealed containers; and

FIG. 26 is a schematic depiction of the apparatus of FIG. 25 providingsubstance to a patient.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

In FIG. 1, a device is indicated generally by the reference numeral 10.In the illustrated embodiment, the device 10 is a vial defining a sealedempty chamber 11 therein for aseptic or sterile filling with asubstance, such as a medicament, pharmaceutical injectable, or vaccine.However, as may be recognized by those of ordinary skill in thepertinent art based on the teachings herein, the invention may beembodied in and otherwise may be applicable to any of numerous differenttypes of devices that are currently known or that later become known,such as containers, syringes, delivery devices, dispensers andprocessing devices. Similarly, the devices may be filled with any ofnumerous different substances that are currently known or that laterbecome known, such as medicaments, pharmaceutical injectables, vaccines,supplements, foods, beverages, liquid nutrition products, and industrialproducts, and in any of numerous different forms, including liquids,gels, powders and gases.

As shown in FIG. 1, the vial 10 includes a vial body 12 and a closure14. In the illustrated embodiment, the body is substantially cylindricaland defines a substantially cylindrical sidewall 16 with an annularaperture 18 at a top end thereof, for sealingly receiving the closure 14thereon, as described further below. The vial body 12 further includesan annular projection 20 spaced from the top end thereof and extendinglaterally outward from the sidewall 16. The vial body 12 may be made ofglass or plastic. However, as may be recognized by those of ordinaryskill in the pertinent art based on the teaching herein, the body may bemade of any of numerous different materials that are currently known orthat later become known. As also may be recognized by those of ordinaryskill in the pertinent art based on the teachings herein, the body maybe configured in any of numerous shapes to receive a closure. Forexample, the body may define a spool-like or “diabolo” shape such asdisclosed in U.S. Pat. No. 7,100,646, issued Sep. 5, 2006, entitled“Sealed Containers and Methods of Making and Filling Same,” which, inturn, claims priority from similarly titled U.S. Provisional PatentApplication No. 60/408,086, filed Sep. 3, 2002, each of which is herebyexpressly incorporated by reference in its entirety as part of thepresent disclosure.

As shown in FIG. 2, FIG. 10A, FIG. 11D and FIG. 13, the closure 14comprises a first closure 22 and a second closure 24. The first andsecond closures 22, 24 are moveable with respect to one another. In theillustrated embodiment, the first and second closures are coupled via aliving hinge 26. However, as may be recognized by those of ordinaryskill in the pertinent art based on the teachings herein, the secondclosure may be connected to either of the first closure or vial body viaany of numerous connections that are currently known or that laterbecome known to allow movement of at least one of the closures relativeto the other. Similarly, the first and second closures 22, 24 need notbe connected in the open position, but rather may be connected only inthe closed position when the second closure overlies and sealinglyengages a penetration aperture in the first closure. Where the first andsecond closures 22, 24 are connected in the open position, they may bemolded in one piece, as shown.

Both the first and second closures 22, 24 include first and secondsubstantially centered recesses 28, 30 respectively, axially extendingfrom the top surfaces of the closures for sealingly receiving thereinfirst and second penetrable septums 32, 34, respectively. The penetrableseptums may be made of any needle-penetrable elastomeric, rubber orrubber-like material that is sufficiently elastic to be penetrated by aneedle. In some embodiments, the septum materials also are sufficientlyelastic to close a resulting penetration aperture after removal of aneedle or like injection member therefrom to thereby reseal itself. Insome embodiments, the first and second penetrable septums 32, 34 areco-molded with the first and second closure portions 22, 24,respectively. In other embodiments, the first and second penetrableseptums 32, 34 are over-molded with the first and second closureportions 22, 24, respectively, e.g., at the same time, as shown in FIGS.11A and 11B. The second closure portion 24 can then be mounted onto thevial body 12 as shown in FIGS. 11C and 11D. However, as may berecognized by those of ordinary skill in the pertinent art based on theteachings herein, the penetrable septums may be configured in any ofnumerous different ways that are currently known or that later becomeknown, to seal the first septum with the second septum. Alternatively,the device may not include a second septum, but rather the resultingpenetration aperture in the first septum may be resealed in anothermanner, as described further below.

As shown in FIG. 3 and FIG. 12, the first closure 22 includes an annularsidewall 36 axially extending from the perimeter of the top surfacethereof, defining an axially extending annular channel 38 between theannular sidewall 36 and the annular wall of the annular recess 28. Theannular channel 38 receives therein a portion of the top end of thecylindrical sidewall 16 of the body 12, when the first closure ismounted atop the body. The top end of the cylindrical sidewall 16 of thebody defines an annular tapered protuberance 40. As can be seen, thetapered protuberance 40 defines a tapered surface 42 on an external sideof the sidewall 16. Directly adjacent to the body tapered protuberance40, opposite the top end of the body, the body sidewall 16 defines alaterally extending annular recess 44, extending inwardly from theexterior of the sidewall.

The bottom end of the annular sidewall 36 of the first closure defines acorresponding annular tapered protuberance 46. As can be seen, thetapered protuberance 46 defines a tapered surface 48 on the interior ofthe sidewall 36. Thus, when the first closure 22 is mounted atop thebody 12, a portion of the sidewall at the top end of the body isreceived within the axially-extending annular channel 38 of the firstclosure, and the annular tapered protuberance 46 of the first closureslides past the opposing annular tapered protuberance 40 of the body andsnaps into the laterally-extending annular recess 44 of the body tocreate a fluid-tight seal therebetween. Another annular recess 50 isdefined between the bottom end of the first closure and thelaterally-extending annular projection 20 of the body.

When the first closure 22 is sealingly mounted atop the body 12, thesealed empty chamber 11 is defined within the body, and the firstpenetrable septum 32 is in fluid communication with the chamber. If thesealed, empty device, and/or the closure 14 and body 12, are sterilized,a sealed, empty, sterile chamber is thus defined therein. Sterilizationof the device, or of the closure, body and/or any component partstherein, may be achieved in any of numerous different ways that arecurrently known, or that later become known, such as by applyingradiation thereto (e.g., gamma, ebeam, UV or other type of sterilizingradiation), or by application of a fluid sterilant (e.g, vaporizedhydrogen peroxide or nitric oxide), and/or the sealed empty chamber maybe sterilized prior to filling with a fluid sterilant as disclosed inU.S. Provisional Patent Application Ser. No. 61/499,626, filed Jun. 21,2011, entitled “Nitric Oxide Injection Sterilization Device and Method,”which is hereby expressly incorporated by reference in its entirety aspart of the present disclosure as if fully set forth herein.

With the first closure 22 mounted atop the body 12, the second closure24 is moveable between a first position (shown in FIG. 2, FIG. 10A, FIG.11D and FIG. 13), spaced away from the first closure 22, and a secondposition (shown in FIG. 4), where the second closure 24 mounts atop thefirst closure 22. In the first position, the second penetrable septum 34is not sealingly engaging the first penetrable septum 32. In the secondposition, on the other hand, the second penetrable septum 34 sealinglyoverlies the penetrable portion of the first penetrable septum 32, thuscreating a mechanical seal, as explained further below. Alternatively,as also explained below, the second septum may be eliminated, and theresulting penetration aperture in the first septum may be resealed inany of numerous different ways that are currently known, or that laterbecome known, such as by laser or other form of radiation, by applyingthermal energy, and/or by applying a liquid sealant, such as liquidsilicone.

As shown in FIG. 5 and FIG. 11B, the second closure 24 includes anannular sidewall 52 axially extending from the perimeter of the topsurface thereof, and is configured to fittingly receive the firstclosure 24 therein when in the second position. The bottom end of thesecond closure annular sidewall 52 defines an annular taperedprotuberance 54. As can be seen, the tapered protuberance 54 defines atapered surface 56 on the internal side of the sidewall 52. When thesecond closure 24 is moved from the first position to the secondposition, the first closure is fittingly received within the secondclosure, the bottom end of the second closure abuts thelaterally-extending annular projection 20 of the body, and the annulartapered protuberance 54 of the second closure snaps into the annularrecess 50 between the bottom end of the first closure and thelaterally-extending annular projection to secure the second closure inthe second position.

When in the second position, the second axially-extending recess 30 ofthe second closure 24, containing the second penetrable septum 34therein, sealingly fits within the first penetrable septum 32, therebysealingly engaging the second penetrable septum atop the penetrableportion of the first penetrable septum. In the illustrated embodiment,as shown in FIG. 4, the first penetrable septum 32 is approximately domeor convex shaped on a side thereof opposite the chamber 11. The secondpenetrable septum 34 is correspondingly approximately dome or convexshaped as well on a side thereof substantially opposite the firstpenetrable septum 32, in order to sealingly mate with the contour of thefirst penetrable septum.

In order to fill the device 10 with a substance, a filling devicepenetrates the first penetrable septum 32, when the second closure 24 isin the second or open position. An exemplary needle is disclosed in U.S.patent application Ser. No. 13/450,306, filed Apr. 18, 2012, entitled“Needle with Closure and Method,” which, in turn, claims priority toU.S. Provisional Patent Application Ser. No. 61/476,523, filed Apr. 18,2011, entitled “Filling Needle and Method,” each of which is herebyexpressly incorporated by reference in its entirety as part of thepresent disclosure as if fully set forth herein.

In some embodiments, a filling device 60, as shown in FIG. 6, isutilized to fill the device 10. The filling device 60 comprises a hollowfilling or injection member 62, a tip 64 formed at one end of thefilling member, two ports 66 in fluid communication with the interior ofthe hollow filling member 62, a first or relatively rigid closure 68,and a second closure or relatively flexible annular shell 70. Thefilling member 62 includes a boss 72 (FIG. 7B) at approximately a middleportion thereof. As can be seen, the boss 72 defines an annularly andaxially extending recess therein for receiving a proximal portion of theclosure 68 and a biasing member 74 that engages and biases the closure,as described further below. In the illustrated embodiments, the twoports 66 are diametrically opposed relative to each other; however, asmay be recognized by those of ordinary skill in the pertinent art basedon the teachings herein, the filling device may define any number ofports that may define any of numerous different configurations andlocations.

The closure 68 and/or the filling member 62 is movable between (i) afirst position wherein the closure closes the ports 66, as showntypically in FIG. 7A, and (ii) a second position opening the ports 66,as shown typically in FIG. 7B. When in the closed position, the closure68 forms a substantially fluid-tight seal between the ports 66 andambient atmosphere. The closure 68 is biased via the biasing member 74in the direction from the second or open position toward the first orclosed position to normally close the ports 66. In the illustratedembodiment, the biasing member 74 is a coil spring. However, as may berecognized by those of ordinary skill in the pertinent art based on theteachings herein, the closure may be biased in any of numerous differentways that are currently known or that later become known, using biasingmembers other than springs. Further, if a spring is used, any ofnumerous different springs or combinations of springs may be used. Inthe illustrated embodiment, the closure 68 is a “shutter” closure thatslides axially over the filling member 62 between the normally closedand open positions. However, as may be recognized by those of ordinaryskill in the pertinent art based on the teachings herein, the closuremay take any of numerous different configurations that are currentlyknown, or that later become known, for performing the function of theclosure as described herein.

The closure 68 extends both annularly and axially about the fillingmember 62 and is slidably mounted on the filling member. The closure 68includes an annular flange 76 adjacent to a proximal end thereof that isengageable with the biasing member 74 for biasing the closure in thedirection from the second or open position toward the first or closedposition. An opposing distal end 78 of the closure 68 is engageable withan annular stop surface 80 of the filling member tip 64 to stop theclosure in the first or closed position. The distal end 78 of theclosure 68 tapers inwardly to define a perimeter substantially flushwith the perimeter of the stop surface 80 and adjacent portion of thefilling member tip 64. As shown in FIGS. 9A and 9B, in alternativeembodiments, the closure 68 (FIG. 9B) and/or the filling member tip 64(FIG. 9A) includes an annular seal 82, between the distal end 78 of theclosure and the tip 64 of the filling member, to further ensure theformation of a fluid-tight seal at the junction of the closure andfilling member. In the embodiment of FIG. 9A, the seal 82 is o-ringshaped and is over-molded to the filling member tip 64. In thealternative embodiment of FIG. 9B, the o-ring shaped seal 82 isover-molded to the distal tip of the closure 68. As may be recognized bythose of ordinary skill in the pertinent art based on the teachingsherein, the seal may or may not be integral with the closure and maytake the form of any of numerous different types of seals or sealingmembers that are currently known or that later become known, tofacilitate the formation of a fluid-tight seal at the juncture of theclosure and filling member. In the illustrated embodiment, the proximalend of the closure 68 is slidably received within the annular recess ofthe boss 72 of the filling member 62, and the biasing member 74 islocated between the rear wall 84 of the boss 72 and the annular flange76.

The flexible closure or shell 70 sealingly encloses the boss 72 of thefilling member 62. In the illustrated embodiment, the flexible shellforms a bellows to allow the shell to axially expand when moving intothe first or closed position (FIG. 7A) and to axially contract whenmoving into the second or open position (FIG. 7B). However, as may berecognized by those of ordinary skill in the pertinent art based on theteachings herein, the flexible shell may take any of numerous differentconfigurations that are currently known, or that later become known, forperforming the function of the shell as described herein. The flexibleshell sealingly engages an outwardly projecting annular flange 86 of theboss 72 near the proximal end thereof, and sealingly engages an annularflange 88 of the closure 68 at the distal end thereof. In theillustrated embodiment, the closure annular flange 88 projects radiallyoutwardly from an approximate mid-portion of the closure 68. The portionof the flexible shell 70 proximally adjacent to the boss annular flange86 includes an annular recess that receives and retains the flange 76and thus integral boss 72. The boss 72 includes corresponding ventingholes 92 located adjacent to the rear wall 84 that are normally sealedby the valve 90. The venting holes 92 are in fluid communication withthe interior recess of the boss 72. The interior of the boss 72 is influid communication with one or more annularly and axially extendingchannels formed between the closure 68 and filling member 62 which, asshown in FIG. 8C and FIG. 15C, are in fluid communication with a chamberto be filled when the closure is located in the second or open position.Thus, when the biasing member 74 is compressed upon movement of theclosure from the first position to the second position, sufficient fluidpressure within the boss 72 (i.e., at or above the venting valve openingpressure) will cause the venting valve 90 to move radially outwardlyrelative to the holes 92 to thereby allow one-way venting of any suchair or other gases into the ambient atmosphere. In addition, asdescribed further below, during filling, any air or other gases (e.g.,nitrogen) that are displaced from the chamber to be filled are allowedto vent through the channels between the closure and filling member and,in turn, through the venting valve 90. When the pressure equalizes, thevalve 90 resiliently returns to its sealing position overlying andengaging the holes 92. In similar fashion, the venting valve 90 allowsone-way venting of air or other gases through the venting holes 92, andinto the shell 72 when a vacuum is present therein. As may be recognizedby those of ordinary skill in the pertinent art based on the teachingsherein, the venting valve may take the form of any of numerous integralor non-integral valves, that are currently known or that later becomesknown, capable of performing the function of the venting valve asdescribed herein.

In the illustrated embodiment, the filling device tip 64 is defined by anon-coring, conically-pointed tip; however, as may be recognized bythose of ordinary skill in the pertinent art based on the teachingsherein, the filling device tip may define any of numerous other tipconfigurations that are currently known, or that later become known,such as a trocar tip. In one configuration, the spring force of thebiasing member 74 is sufficient to allow the filling device 60 topenetrate a septum of an opposing device while maintaining the closure68 in the closed position during penetration of the closure through theseptum and until the annular flange 88 of the closure engages anexterior surface of the septum (or other exterior or stop surface of thedevice to be filled) to cause relative movement of the closure andfilling member against the bias of the biasing member 74 from thenormally closed position to the open position and, in turn, expose thesterile filling device ports 66, 66 within the sterile device chamber.

A filling line attachment fitting 94 is formed on a proximal end of thefilling member 62. In the illustrated embodiment, the attachment fitting94 is a barbed fitting for attachment to a filling line (not shown). Asmay be recognized by those of ordinary skill in the pertinent art basedon the teachings herein, any of numerous different types of fittings,connections or connectors that are currently known, or that later becomeknown, equally may be employed for connecting the filling device to afilling or other type of line or conduit. For example, the proximal endof the filling device may define a male or a female connector foraseptically or sterile connecting to the other of the male or femaleconnector attached to a filling line, as disclosed in U.S. ProvisionalPatent Application No. 61/641,248, filed May 1, 2012, entitled “Devicefor Connecting or Filling and Method” and similarly titled U.S.Provisional Patent Application No. 61/794,255, filed Mar. 15, 2013; U.S.Provisional Patent Application No. 61/635,258, filed Apr. 18, 2012,entitled “Self-Closing Connector;” and similarly titled U.S. ProvisionalPatent Application No. 61/625,663, filed Apr. 17, 2012, each of which ishereby expressly incorporated by reference in its entirety as part ofthe present disclosure as if fully set forth herein.

The filling device 60 may be used to aseptically or sterile fill fluidsthrough the first penetrable septum 32 and into the chamber 11 of thedevice 10. As shown in FIG. 8A, FIG. 10B and FIG. 15A, prior topenetrating the first septum 32, and when the filling device tip 64 isexposed to the ambient atmosphere, the closure 68 is in the closedposition sealing the ports 66 with respect to ambient atmosphere tothereby maintain the sterility of the ports and of the interior of thefilling device. As shown in FIG. 8B and FIG. 15B, upon penetrating thefirst septum 32, the closure 68 remains interposed between the ports 66and the first penetrable septum 32 to substantially prevent contactbetween the ports and the septum. When the ports 66 are located withinthe chamber 11, the bottom surface of the annular flange 88 of theclosure engages the top surface of the first closure 22 and preventsfurther movement of the shutter closure 68 relative to the first closure22. Further penetration of the filling device 60 into the chamber of thedevice 10 causes the filling member 62 and filling device tip 64 toslide relative to the shutter closure 68 against the bias of the biasingmember 74 to, in turn, move the ports 66 to the open position. As thebiasing member 74 is compressed with further movement of the shutterclosure from the closed position to the open position, any fluidpressure within the shell 72 above of the venting valve opening pressureis allow to flow through the venting valve 90 into the ambientatmosphere. In the open position of FIG. 8C and FIG. 15C, the fluid orother substance within the filling device is permitted to flow throughthe open ports 66 and into the chamber 11. Any fluid within the chamber11 that is displaced by the substance flowing into the chamber isallowed to vent through the channels formed between the shutterenclosure 68 and filling device 62 and, in turn, through the ventingvalve 90. Since the sterile ports 66 are never exposed to the ambientatmosphere throughout the filling process, the ports, interior of thefilling device, and fluid flowing therethrough, are not contaminatedand/or are maintained aseptic or sterile as the fluid is injected orotherwise filled into the chamber 11.

In accordance with an embodiment, the method of sterile or asepticfilling of the device 10 comprises the following steps:

-   -   (a) Penetrating the elastic septum 32 of the device 10 with the        tip 64 of the injection member 62. As described above, the        device 10 defines a sealed, empty, sterile chamber 11 in fluid        communication with the elastic septum 32;    -   (b) During the penetrating step, and as shown typically in FIGS.        18A and 18B, forming an annular interface 98 between the elastic        septum 32 and the injection member 62 extending axially between        a penetration point 100 on an interior surface of the elastic        septum in fluid communication with the sterile chamber, and an        exterior surface 102 of the septum engaging the injection        member. Movement of at least one of the injection member 62 and        elastic septum 32 relative to the other during the penetration        step decontaminates the injection member 62, including the        penetrating tip 64 and shutter closure 68 thereof, by at least        one of (i) friction between the elastic septum 32 and injection        member 62 at the annular interface 98, and (ii) elongation of        the elastic septum 32 at the annular interface 98. In order to        enhance the decontamination, the coefficient of friction of the        septum-engaging surface of the injection member 62 is less than        the coefficient of friction of the penetrated portion of the        elastic septum 32.    -   (c) Introducing a substance, such as a vaccine, pharmaceutical        injectable, liquid nutrition product, or other liquid, cream,        gel, powder or gas, through the ports 66 of the injection member        62 and into the sterile chamber 11 of the device 10;    -   (d) Withdrawing the injection member 62 from the elastic septum        32;    -   (e) Allowing the elastic septum 32 to reseal itself at the        penetration aperture resulting from withdrawal of the injection        member 62; and    -   (f) Maintaining the chamber 11 sterile throughout steps (a)        through (e).

As shown best in FIGS. 18A and 18B, the annular interface 98 is definedby a portion of the penetrated elastic septum extending annularly aboutthe injection member 62 substantially throughout an axial distance “X”extending between the interior and exterior points of contact 100 and102, respectively, between the penetrated septum and injection member.In some embodiments, the axial distance is X at least about ½ mm, otherembodiments at least about 1 mm, and in further embodiments at leastabout 1⅓ mm. In some embodiments, and as shown typically in FIGS. 18Aand 18B, the annular interface 98 between the elastic septum andinjection member defines a substantially inverted, frusto-conical shape.

In this embodiment, the penetrating step is performed in an ambientenvironment defining a level of contamination greater than about class100 or ISO 5. Other embodiments comprise performing the above steps a)through e) in an ambient environment defining a level of contaminationgreater than about class 100 or ISO 5, and even in an ambientenvironment defining a level of contamination greater than about class100 or ISO 5 and less than or equal to about class 100,000 or ISO 8.

In some embodiments, the de-contaminating of the injection memberachieves at least approximately a 3 log reduction in bio-burden at theannular interface 98 between the elastic septum 32 and injection member62, in other embodiments at least approximately a 5 log reduction inbio-burden at the annular interface 98 between the elastic septum andinjection member, and in further embodiments at least approximately a 6log reduction in bio-burden at the annular interface 98 between theelastic septum and injection member.

In FIG. 19, an alternative embodiment of an elastic septum is indicatedgenerally by the reference numeral 132. The elastic septum 132 issubstantially similar to the elastic septum 32 described above, andtherefore like reference numerals preceded by the numeral “1”, or thenumeral “2” instead of the numeral “1”, are used to indicate likeelements. As can be seen, the elastic septum 132 includes a penetrationzone having an approximate dome-shape defining a substantially convexexterior surface 202, and a substantially concave interior surface 204opposite the convex exterior surface. One advantage of the dome shape isthat it enhances the pressure exerted by the elastic septum onto theinjection member during the penetrating step. In some embodiments, thede-contaminating of the injection member 62 includes exerting pressurewith the elastic septum 32 onto the injection member 62 at the annularinterface between the elastic septum and injection member and, in turn,killing organisms at the interface. In some such embodiments, theexerting pressure on the injection member includes penetrating asubstantially dome or convex shaped portion of the elastic septum asdescribed in the exemplary embodiments herein. The interior surface 204of the septum 132 defines a relatively recessed surface 206 extendingsubstantially about the penetration zone. In the illustrated embodiment,the relatively recessed surface is a continuous, annular groove 206 thatextends annularly about and adjacent or contiguous to the zone ofpenetration. One advantage of the annular groove or like structure isthat it reduces the strain on the interior surface of the septum withinthe zone of penetration of the injection member during the penetratingstep to, in turn, maximize the axial distance X of the annular interface98.

The penetration zone of the elastic septum 132 includes a recess 208formed therein defining a reduced thickness “t” of the elastic septum.During the penetration step described above, the tip 64 of the injectionmember 62 is received within the recess 208 and penetrates the septum atits penetration zone of reduced thickness “t”. In the illustratedembodiment, the penetration zone recess 208 defines a substantiallyfrusto-conical shape. As indicated above, the injection member 62includes a penetrating tip 64 defining a first included angle “A1” (FIG.18A), and the penetration zone recess 208 defines a second includedangle “A2” that is substantially the same as the first included angleA1. In other embodiments, the injection member 62 includes a penetratingtip 64 defining a first included angle A1, and the penetration zonerecess 208 defines a second included angle A2 that is greater than thefirst included angle A1. The interference between the included angle A1of the penetrating tip 64 and included angle A2 of the penetrationrecess is selected to enhance the de-contamination of the injectionmember.

One advantage is that movement of at least one of the injection member62 and elastic septum 32 relative to the other during penetration of theseptum decontaminates the injection member 62, including the penetratingtip 64 and shutter closure 68 thereof, by at least one of (i) frictionbetween the elastic septum 32 and injection member 62 at the annularinterface 98, and (ii) elongation of the elastic septum 32 at theannular interface 98. Various factors can affect the de-contaminationeffect as hereinafter summarized.

The material of the elastic septum must impart a sufficient frictionforce to the injection member while nevertheless generating as fewparticles as possible during the penetration step. As a general matter,the higher the elongation of the material, the lower the number ofcracks generated by friction and the greater the elongation of theseptum material during the penetration step. In some embodiments, theelongation differential of the different components of the septummaterial is minimized to enhance the degree of elongation of thematerial prior to cracking during penetration. It also is generallydesirable to use a septum material that exhibits relatively low, orminimal creep, in order to ensure relative rapid self-closure of theseptum after withdrawal of the injection member therefrom to preventexposure of the ambient environment to the sterile chamber. The septummaterial in some embodiments is molded, such as by injection, blow,compression molding, etc. In one embodiment, the elastic septum materialis a silicone have a hardness within the range of about 1 shore A toabout 100 shore A, such as within the range of about 20 shore A to about80 shore A.

The configuration of the elastic septum also can affect thede-contamination effect. For example, a dome or convex/concave shape maybe imparted to the penetration zone of the septum so that duringpenetration a radial compression is exerted by the septum onto theinjection member, which in some embodiments is substantially maximizedat the outset of the penetration of the septum by the injection member.Accordingly, the shape of the septum may be selected to maximize orenhance the radial compression exerted by the septum against theinjection member during the penetration step.

In some embodiments, the crack needed to perforate the septum occurs atsubstantially the maximum elongation of the septum material, and isbased on the desired stroke length of the injection member during thepenetration step. Accordingly, based on the desired stroke length, theelongation of the septum prior to or at about the time of perforation ofthe septum is maximized.

With respect to the thickness of the septum, as a general matter, thelonger the axial distance X of the annular interface between the elasticseptum and injection member, the greater the de-contamination. Forming arecess in the penetration zone, such as the frusto-conical shaped recessdescribed above, increases the axial length X of the annular interface,without significantly increasing the force required to penetrate theseptum due to the reduced thickness of the septum at the penetrationrecess. The diameter and included angle of the penetration recess isdetermined based on, and balanced against, the diameter and includedangle of the penetration tip of the injection member, to maximize thede-contamination effect by friction and elongation while maintaining anappropriate penetration force. The side wall of the penetration recesswipes and decontaminates the injection member, and the reduced thicknesst of the septum is sufficient to de-contaminate the tip of the injectionmember not wiped upon passage through the penetration recess.

The ratio of the septum thickness to the outer diameter of the injectionmember also may be controlled to enhance the de-contamination effect.The internal pressure applied by the septum onto the injection memberduring penetration can be significant with respect to achieving thedesired de-contamination of the injection member. For the minimuminternal pressure to be applied, the injection member diameter must belarge enough to be sufficiently wiped over the smallest septum thicknessto be pierced. As a general matter, the larger the septum thickness fora given injection member outer diameter, the greater is the deformationof the septum and the longer the penetration stroke. The product of theinternal pressure times the thickness of the penetration zone must begreater than a threshold required to de-contaminate the injection memberin a certain level of decontamination in the ambient environment. Thesmaller the internal pressure, the greater should be the thickness ofthe septum. The axial distance of the annular interface is the minimumamount of de-contamination that occurs by elongation. When the injectionmember depresses the septum and creates the corresponding concavity (orfrusto-conical shape) in the septum, the annular interface elongatesuntil the elastomeric material reaches its maximum elongation beforecracking. During this phase, the germ density initially high beforeelongation is reduced by the elongation effect alone.

As indicated above, in some embodiments the coefficient of friction ofthe septum is greater than the coefficient of friction of the injectionmember to enhance the friction at the interface and the resultantde-contaminating effect. Also, as a general matter, the greater theouter diameter of the injection member, the greater should be thethickness of the penetrated septum. Additionally, the hardness (ordurometer) of the septum also affects the pressure applied by the septumonto the tip. In some embodiments, the durometer of the septum is withinthe range of about 20 Shore A to about 50 Shore A, such as within therange of about 25 Shore A to about 45 Shore A. In some such embodiments,the septum thickness is within the range of about ½ to about two timesthe largest diameter of the tip of the filling member.

The septum deformation after cracking and crack dilation also has aneffect on the de-contamination effect. The strain on the inner surfaceof the septum tends to pull the pierced septum outwardly and, in turn,reduces the axial distance of the annular interface, shown typically asX in FIG. 18B. In some embodiments, the inner surface of the septum isconfigured to reduce the strain thereon and thus maximize the distance Xof the annular interface. The greater is the distance X of the annularinterface, the greater is the distance between the sterile chamber andthe potentially contaminated exterior surface of the injection member,and thus the lower is the likelihood of any germs being pushed by theinjection member through the septum and into the sterile chamber. Theannular groove 206 or like recess formed on the interior surface of theseptum adjacent to the zone of penetration reduces the strain on theinterior surface during penetration thereof by the injection member.During penetration, the groove dilates, and the strain on the inner edgeor wall of the groove is reduced to, in turn, allow greater elongationof septum by the injection member and thus a larger axial distance X ofthe annular interface.

The material of the filling member 62 and the septum 32 also may beselected to enhance the decontamination effect. The present inventor hasdetermined that the use of a plastic filling member provides theappropriate friction coefficient range to enhance the effect ofdecontamination by friction force. Advantageously, the plastic materialis also easier to mold, and thus easier to manufacture and assemble. Thepresent inventor also has determined that a septum made of a homogeneouselastic material defining a substantially homogeneous density willenhance the decontamination effect. In some embodiments, the filling orinjection member is formed of plastic, such as any of numerous differentthermoplastics, including the liquid crystal polymers (LCP) that arehighly crystalline, thermotropic (melt-orienting) thermoplastics andsold under the trademark Vectra™ by Celanese Corporation, or graphene.In some such embodiments, the elastic septum is made of silicone. Inother embodiments, the elastic septum is made of a vulcanized rubber ora thermoplastic. However, as may be recognized by those of ordinaryskill in the pertinent art based on the teachings herein, the fillingmember and septum may be made of any of numerous different materialsthat are currently known, or that later become known, to perform thefunctions of the filling member and septum disclosed herein.

The configuration of the filling member itself also can enhance thedecontamination effect. The included angle of the tip of the fillingmember affects the progressively increasing thickness of the tip, andthe diameter of the filling device, i.e., the outer diameter of theshutter closure. As the filling member penetrates through the elasticseptum, the internal pressure applied by the septum onto the tip, andthereafter onto a portion of the rigid closure increases proportionallyto the progressively increasing tip diameter, resulting from theincluded angle of the tip. In some embodiments, the included angle ofthe tip of the piercing member is within the range of about 20 degreesto about 40 degrees, and such as about 30 degrees.

The present inventor has determined that the wiping effect on a fillingmember tip by a septum having properties as aforementioned may achieveat least approximately a 3 log reduction in bio-burden, which is aboutthe reduction achieved by known UV pulse (5 second) sterilizationtechniques, and up to approximately a 6 log reduction in bio-burden.Another advantage is that the filling device may sterile fill asubstance into the device without the need to decontaminate the septumof the device or the tip of the filling device prior to filling. Thecombination of the maintained sterility of the ports and interior of thefilling device, as well as the decontamination effect provided by theelastic septum effectively sterilize the tip of the filling member uponpenetration of the filling member through the septum. Therefore, oneadvantage of such embodiments is that it allows substantially sterilefilling of fluids within a non-aseptic, non-sterile or relatively lowsterility assurance level (“SAL”) environment, such as a controlled,non-classified environment. Such an environment may define a level ofcontamination greater than about class 100 or ISO 5 and less than orequal to about class 100,000 or ISO 8. In such a controlled,non-classified environment, an operator may wear a lab coat, hair netand gloves, and if desired, the filling device may be installed in aroom with closed room door access. However, there is no need for a cleanroom, isolator, or any of the other numerous controls and requirementsrequired by the prior art sterile or aseptic filling methods andsystems.

As shown in FIG. 15D, after the chamber 11 is filled as desired, thefilling device 60 is withdrawn from the first septum 32. As the fillingdevice is withdrawn, the biasing member 74 biases the rigid closure 68downwardly or in the direction of the septum 32. Therefore, as thefilling member 62 is withdrawn, it is moved axially relative to theshutter closure 68 to, in turn, move the ports 66 into the closedposition behind the closure. The shutter closure 68 is configured tosubstantially prevent contact between the filling device eyes or ports66, and as can be seen, the sliding shutter or closure is closed overthe filling device eyes or ports prior to their passage through theseptum and/or withdrawal therefrom. When the distal end 78 of theclosure 68 sealingly reengages the stop surface 80 of the filling devicetip 64, the closure is in the closed position, and is maintained in theclosed position by the downward force or bias of the biasing member 74.Thus, during, upon, and before, withdrawal of the filling device 60 fromthe first septum 32, the closure 68 sealingly closes the ports 66 andprevents contamination of the ports or interior of the filling device.

As indicated above, the first septum 32 is engineered in a manner knownto those of ordinary skill in the pertinent art to self-close andthereby ensure that the head loss left by the residual filling deviceinjection aperture 96 after the tip of the filling device is withdrawnsubstantially prevents fluid ingress therethrough. Thereafter, as shownin FIG. 4, the second closure portion 24 is moved from the firstposition, and snaps into the second position, and the unpenetratedsecond septum 34 overlies and seals the injection aperture 96 in thefirst septum 32 from the ambient atmosphere. This forms a filled, sealeddevice as shown in FIG. 10C, FIGS. 14, FIG. 16A, and FIG. 17A. Prior tomoving the second closure 24 from the first position to the secondposition, the exterior surface of the first closure 22 and/or theinterior surface of the second closure 24 may be sterilized, such as isshown in the example of FIG. 16A, in order to prevent any contaminantsfrom between trapped between the first and second septums 32 and 34,respectively, after closure of the second closure to the first closure.Sterilization of these surfaces may be performed in any of numerousdifferent ways that are currently known, or that later become known,including without limitation, by the application of radiation thereto,such as e-beam, laser or UV radiation, by the application of a fluidsterilant, such as vaporized hydrogen peroxide (“VHP”) or nitric oxide(“NO”), or by heated gas.

If desired, a further closure may be applied over the second closure 24and/or second septum 34, such as an adhesive-backed foil layer thatoverlies the second septum 24 and is adhesively attached to the secondseptum or second closure, to provide an additional barrier such as toprevent moisture-vapor transmission (“MVT”). When ready for use, theadhesive-back foil layer or other additional MVT barrier may be manuallyengaged and removed to expose the second septum. Then, as shown in FIG.10D and FIG. 17B, a syringe needle or like withdrawal device may bepierced through the first and second septums and placed into fluidcommunication with the interior chamber 11 and the fluid or othersubstance therein to withdraw the fluid or other substance from thechamber and into the syringe to, for example, inject the withdrawnsubstance into a person, patient or other subject. In some embodiments,the first and second septums may be pierced one or more times as desiredto withdraw substance from the chamber 11 until the chamber is empty asshown in FIG. 10E.

In other embodiments, the second closure is initially a separate pieceand is not connected to the first closure as disclosed in the followingco-pending patent application which is hereby expressly incorporated byreference in its entirety as part of the present disclosure: Co-pendingU.S. Provisional Application entitled “Device With Penetrable Septum,Filling Needle and Penetrable Closure, and Related Method” filed on evendate herewith. After the first closure is pierced and the device isfilled with a substance, the second closure is then fixedly secured,such as by a snap fit as described above, to the first closure tosealingly engage the first and second septums, and seal the resultingpenetration aperture in the first septum. The second closure can bepre-sterilized prior to assembly, or can be surface sterilized asdescribed above prior to assembly to the first closure. The secondclosure can be automatically assembled to the first closure with any ofnumerous different assembly devices that are currently known, or thatlater become known, such as a pick and place robotic assembly device, orother suitable fixture that can automatically assemble the secondclosure to the first closure. A closure assembly station can be locateddownstream of the needle penetration and filling station to assemble thesecond closure to the first closure upon or following withdrawal of thefilling needle from the first closure.

In other embodiments, the second closure is eliminated, and theresulting penetration aperture in the elastic septum is resealed in anyof numerous different ways that are currently known, or that laterbecome known, such as by resealing the resulting penetration aperturewith a liquid sealant, a thermal seal, and/or a chemical seal. Someembodiments further comprise transmitting radiation onto the resultingpenetration aperture to effect or further effectuate the seal.

In another embodiment, the devices to be sterile filled are cartridgeswherein each cartridge includes a sealed, empty, sterile chamber, and anelastic septum in fluid communication with the sterile chamber. Thefilling device includes one or more filling members, and each fillingmember is connected in fluid communication with a respective source ofsubstance, product or product component to be filled therethrough. Acomputerized controller controls the respective filling devices to fillinto each cartridge one or more respective components, a label isprinted to indicate the component(s) filled into the respectivecartridge and any other desired information, and the label is applied tothe respective filled cartridge. The resulting penetration aperture orapertures in the elastic septum are resealed by a mechanical seal, aliquid sealant, a thermal seal, and/or a chemical seal. If desired,radiation may be transmitted onto the resulting penetration aperture toeffect or further effectuate the seal. Each cartridge may include asterile connector for purposes of withdrawing the component orcomponents filled into the sterile chamber. Exemplary such sterileconnectors are disclosed in the following co-pending patentapplications, each of which is hereby expressly incorporated byreference as part of the present disclosure: U.S. patent applicationSer. No. 13/080,537, filed Apr. 5, 2011, entitled “Aseptic Connectorwith Deflectable Ring of Concern and Method”, which claims the benefitof similarly titled U.S. Provisional Application No. 61/320,857, filedApr. 5, 2010; U.S. patent application Ser. No. 13/874,839, filed Apr.17, 2013, entitled “Device for Connecting or Filling and Method”, whichclaims the benefit of similarly titled U.S. Provisional PatentApplication No. 61/641,248, filed May 1, 2012, and similarly titled U.S.Provisional Patent Application No. 61/794,255, filed Mar. 15, 2013; andU.S. patent application Ser. No. 13/864,919, filed Apr. 17, 2013,entitled “Self-Closing Connector”, which claims the benefit of similarlytitled U.S. Provisional Patent Application No. 61/635,258, filed Apr.18, 2012, and similarly titled U.S. Provisional Patent Application No.61/625,663, filed Apr. 17, 2012, each of which is hereby expresslyincorporated by reference in its entirety as part of the presentdisclosure as if fully set forth herein.

Turning now to FIGS. 20-23, an apparatus 300 for filling and resealingsealed containers or other devices is shown. The apparatus describedbelow can provide small-scale sterile filling, for example: forpharmaceutical and biotechnology research and development, universityteaching, research, and development, clinical trials, analyticallaboratories; at pharmacies, hospitals, doctor's offices, extended carefacilities, and/or emergency and rescue operation areas for on-demanddispensing and production for customers and patients; at food processingplants; at facilities for manufacturing and formulation trials,research, and production; and can be used in emerging markets andcountries where large scale production may not be feasible and/orcost-effective.

Apparatus 300 is capable, in at least some embodiments, of employing thefilling process described above, using device 10 and filling device 60.However, those skilled in the art will appreciate that other types ofdevices and containers and/or filling devices and needles can be used inapparatus 300. For example, container 301 can be formed from glassand/or plastic and can be of various shapes, sizes, and dimensions,including, for example, vials, tubes, pouches, bottles, etc., withvolumetric dimensions of about 2 ml up to about 500 ml. In someembodiments developed by the inventor, the apparatus 300 can sterilefill up to about 200 units per hour. However, as should be understood bythose of ordinary skill in the art, the preceding listed devices, sizes,and unit output are merely exemplary, and other devices and sizes thatare currently known or will become known can be filled, and the fillingapparatus can be configured as suitable for a particular device andoutput requirement.

FIG. 20 shows a perspective front view of apparatus 300 that isconfigured to fill and reseal a container 301. The apparatus 300 definesa filling or processing space 310 in which the filling and resealingprocess is performed. Container 301, as shown, is held by a movablesupport 302 during the filling and resealing process. The support isconfigured to hold the container 301 substantially without movingrelative to the support, especially in a vertical direction, during thefilling and resealing process. The support is movable within theprocessing space 310 between the various steps, and/or stations of theapparatus 300, of the filling and resealing process, as furtherdescribed below.

Support 302 can be moved during the filling and resealing processmanually or in an automated process by a servo-motor or other electricmotor drive. In other embodiments, other mechanical and/or electricalmechanisms are employed to convey the container 301 through theapparatus 300 on support 302. For example, in other embodiments, themovable support 302 is transported by a belt drive, gears, a belt-drivencarriage, a screw motor, a conveyor, a loop-conveyor, ismagnetically-driven, hydraulically-driven, pneumatically-driven, handcrank driven, or operated by any other mechanism that is currently knownor that later become known. Furthermore, the drive mechanism and support302 is configured to stop the support 302 at specific points as it ismoved, and securely holds or locks the support, and thus the container301, at the desired position to prevent undesired movement of thecontainer 301 or support 302. The movement of the support 302 iscontrolled, by electrical and/or computer components connected theretothat are contained within apparatus 300 in a manner that should beunderstood by those of ordinary skill in the art. Control panel 315provides a control interface between a user and the apparatus 300 tocontrol components, by which the user can operate the apparatus. In theillustrated embodiment, to move container 301 through the apparatus 300and the filling or processing space 310 thereof, the support 302 ismounted on a bi-directional conveyer that runs along a track 307, suchas a channel or path, and a motorized mechanism moves the conveyor, andconsequently the support 302 attached thereto, and the container 301mounted thereon, in a first direction through the apparatus 300, to filland then seal the container 301, and then move the support 302 back in asecond direction opposite to the first direction, to remove thecontainer 301 to outside the processing space 310, where the user canunmount the filled and sealed container. In other embodiments, the usermanually moves support 302, and/or container 301 into the processingspace 310, to the various stations in the processing space, to fill andthen seal container 301, as described below, and then out of theprocessing space 310 to remove the container from the support 302.

The filling process described below takes place within the processingspace 310 of apparatus 300. Processing space 310 is partially defined bythe housing 318 of the apparatus 300, and further defined by a hingeddoor 308 that, in the closed position encloses the components of theapparatus 300 that interact with the container 301, and in the openposition, as seen in FIG. 20, allows access to the processing space 310and components therein. Door 308 is an opaque plastic material, but inother embodiments is plastic, glass, acrylic, and/or composite materialthat is transparent or opaque, or formed from other suitable materialsas will be appreciated by those of ordinary skill on the art. Further,the door 308 in some such embodiments is of a material and/or coatedwith appropriate coatings to prevent ultraviolet radiation, laserradiation, ebeam radiation, and/or other types of radiation from passingtherethrough when the door is closed to protect the user. In addition toproviding a protective barrier for radiation, door 308 allows for a useror operator of apparatus 300 to access the components that are withinthe processing space 310, including for maintenance and repair, and/orto provide access to the container 301 once it is conveyed into theprocessing space 310 on support 302. Further, although shown as a hingeddoor 308, the door of apparatus 300 in other embodiments is a slidingdoor or a removable door or panel that, when attached to apparatus 300,defines the processing space 310.

To begin the process of using apparatus 300, it is turned on, to provideelectrical power to the components and initialize theelectronic/computer components. The user then operates the apparatus viathe control panel 315. The user removably mounts a removable fillingdevice 304, such as a closed needle 60 as described above, an open-eyeneedle, or any other type of suitable filling device into apparatus asshown in FIG. 20. In the illustrated embodiment, the filling device 304is a closed needle of the type described above. The filling device 304is connected to a source of substance to be filled into the container301, as further described below.

In this embodiment, the needle 304 includes a removable cap 311extending over the tip of the needle 304 to help keep contaminants offthe filling device 304 and help prevent accidental needle sticks to theuser. When the user initiates the filling process, the cap 311 isremoved from needle 304 to expose the piercing tip of the fillingdevice, such as the illustrated needle. As seen in the drawing, thesupport 302 includes a cap grip 319. In the cap 311 removal process, thesupport 302 is transported into the processing space 310 so that the capgrip 319 is aligned directly below the needle 304 and cap 311. Thefilling device 304 is then moved downwardly in a manner more fullydescribed below, until the cap 311 is engaged in the cap grip 319 asseen in FIG. 20. The needle 304 is then retracted upward, disengagingthe cap 311 from the filling device 304. In the illustrated embodiment,the filling device 304 and cap 311 define a snap on/off engagement, forrepeatable detachment and attachment of the cap 311 and filling device304. However, as should be appreciated by those of ordinary skill in theart, other types of mechanisms allowing detachment and reattachment ofthe cap 311 to the filling device 304 are used in further embodiments.

As seen in FIGS. 20 and 21, the cap 311 remains mounted in the cap grip319 of support 302 during the remainder of the filling process.

Alternatively, the cap 311 is stored on cap holder 312 during thefilling process. In this embodiment the holder 302 is moved further intothe processing space 310 (to the left in FIG. 20) until the cap 311 isaligned directly below the cap holder 312. The cap holder 312 is thenmoved downwardly until it engages and releasably retains the cap 311.The cap holder 312 is then retracted upward with the cap 311 engaged toit, removing the cap 311 upwardly out of the cap grip 319. The cap 311is thus engaged by the cap holder 312 in a storage position during thefilling and sealing process. As illustrated, the cap 311 and cap holder312 define a snap on/off engagement, for repeatable detachment andattachment of the cap 311 and filling device 304. However, as should beappreciated by those of ordinary skill in the art, other types ofmechanisms allowing attachment and detachment of the cap 311 to the capholder 312 are used in further embodiments.

After the cap 311 is removed from the filling device 304, the support302 will then move back out of the processing space 310, to its originalposition (far right in FIG. 20). This process of cap removal is anautomated process initiated by the user via the control panel 315, butin other embodiments, the cap 312 is manually removed and stored by theuser.

Next, a user installs, mounts, and/or removably attaches a vial or othercontainer 301 onto the support 302 as seen in FIG. 20, to be filled.Once the container 301 is mounted to support 302, the filling andresealing process is initiated by the user via the control panel 315.The filling process is then performed in a fully automated manner by theelectronic components of the apparatus 300. In other embodiments, thefilling process is performed manually, and/or with a combination ofautomatic and manual steps.

During the filling and resealing process, container 301 is moved on thesupport 302 to a series of positions or stations, each performing adifferent step in the process. The container 301 is first moved to adecontamination and/or sanitizing station, underneath a decontaminationand/or sanitizing device 303 that is configured to decontaminate and/orsanitize the top of the container 301, which as illustrated includes apenetrable septum, as described above. Sanitization and/ordecontamination of the top of the container 301, including the septum isthen performed using ultraviolet (UV) radiation emitted by thesanitizing device 303 onto the container 301 for a sufficient time toadequately sanitizing the septum. Sanitizing device 303 is a low-powerUV-emitting LED (light emitting diode). Other embodiments use othertypes of UV-emitting devices, e.g., a UV-emitting light bulb, a UVlaser, etc.

It should be appreciated by those of ordinary skill in the art that inother embodiments the sanitizing device 303 is a different type ofdecontamination device that is currently known, or that later becomesknown, such as radiation emitting devices (e.g., gamma, ebeam, thermallaser or other type of sterilizing radiation), or a fluid sterilantapplicator (e.g, vaporized hydrogen peroxide or nitric oxide). Inalternative embodiments, the container 301 is sterilized, sanitized,and/or decontaminated prior to being placed in apparatus 300, asdescribed above, such that the apparatus 300 does not include thesanitizing device 303.

After the container 301 is sanitized, the container 301 is moved to afilling station, including the filling device 304, to be filled asdescribed above. For example, the support 302 and container 301 aremoved to a position underneath the filling device 304. The fillingdevice 304 illustrated in FIGS. 20 and 21 is a closed, non-coringneedle, but in other embodiments is another type of needle or injectionmember. The filling device 304 is moved downward into contact with theseptum of the container 301 by a servo-motor, or in alternativeembodiments, another mechanical and/or electrical mechanism, forexample, a manual lever or electric motor, and punctures the septum. Thefilling device 304 then passes through the septum and forms an aperturetherethrough. Once the filling device 304 punctures the septum andpasses therethrough into the chamber of the device 301, a port oropening of the filling device 304 will be in fluid communication withthe chamber of container 301 and can dispense substance into thechamber. Substance is pumped by the apparatus 300 and into and throughthe filling device 304 and into the chamber of the container 301 by aperistaltic pump (not shown) contained within apparatus 300. The pumppumps the substance to be filled from a source of the substance,discussed further below. Those skilled in the art will appreciate thatother types of pumps are employed to pump substance through the fillingdevice 304 and into the chamber of the container 301 in alternativeembodiments.

Control panel 315 is used to program and/or set a specific and/orprecise amount or volume of substance that is to be dispensed into thechamber of the container 301. The apparatus 300 includesmicroprocessors, electrical mechanisms, and/or other control devices andfunctions to control or meter the flow of substance through the fillingdevice 304. In an exemplary embodiment, the apparatus 300 controls theflow volume by operating the pump for a predetermined interval of timethat will pump the programmed amount. In other embodiments, flow amountis controlled in alternative manners that are currently known or maybecome known. In this manner, the fill volume of the container 301 canbe programmed by the user via the control panel 315, e.g., about 2 ml upto about 500 ml, and the apparatus 300 will pump the programmed amountinto the container.

After the container 301 is filled, the filling device 304 is retractedor removed from the septum of the container 301, i.e., moved upward backinto the position shown in FIG. 20. As described above, where the septumis resilient or self-closing, the aperture formed in the septum willclose in a manner sufficient to substantially prevent leakage or passageof contaminants through the aperture until resealing can be performed.

To reseal the container, the container 301 is next moved or conveyed bythe support 302 within the processing space 310 to a sealing stationthat includes a liquid sealant dispenser 305 and then a sealer device306. First, the container 301 is conveyed by support 302 to the sealantdispenser 305. Sealant dispenser 305 is configured to dispense a liquidsealant onto the septum of the container 301 to cover and/or seal theaperture that was formed during the filling step by the filling device304. The sealant is supplied from a cartridge stored within theapparatus 300, which is replaceable/refillable from an access panel onthe back side and/or top of the apparatus 300, similar in function to aprinter cartridge.

After the liquid sealant is dispensed to cover the aperture, the support302 conveys the container 301 to the sealer device 306 that isconfigured to cure the dispensed sealant and seal the aperture, therebyforming a hermetic, sanitary sealed container 301 with a substancestored therein. In the illustrated embodiment, the sealant dispenser 305deposits a UV curable liquid sealant drop onto the septum to cover theaperture, and then the sealer device 306 applies ultraviolet radiationto the liquid sealant drop using a UV LED (or in alternativeembodiments, another UV source) to cure the sealant and form a hermeticseal, for example, as disclosed in co-pending U.S. patent applicationSer. No. 13/745,721, filed Jan. 18, 2013, entitled “Device withCo-Molded Closure, One-Way Valve, Variable-Volume Storage Chamber andAnti-Spritz Feature and Related Method,” which is hereby expresslyincorporated by reference in its entirety as part of the presentdisclosure.

Alternatively, other embodiments utilize different methods of sealingthe filling device aperture formed in the septum. These include amechanical seal, a thermal seal, and/or a chemical seal. In embodimentsutilizing a mechanical seal, the sealant dispenser 305, 306 is omittedfrom apparatus 300. Examples of mechanical seals and methods aredisclosed, for example, in U.S. patent application Ser. No. 13/080,537,filed Mar. 14, 2014, entitled “Device with Sliding Stopper and RelatedMethod,” which claims the benefit of similarly titled U.S. ProvisionalApplication No. 61/799,423, filed Mar. 15, 2013, which are herebyincorporated by reference in their entireties as part of the presentdisclosure. In some such embodiments, the sealer 306 is formed as atongue or other pressure application mechanism that pushes a stopper orother seal into place over the aperture to form a hermetic seal betweenthe container 301 chamber and the ambient atmosphere as described, forexample, in the above-listed patents and patent applications.

In other embodiments, the septum of container 301 is a heat-resealableseptum, and is resealed by the application of laser radiation or energy,to hermetically seal the filled substance within the chamber ofcontainer 301 from the ambient atmosphere. Such embodiments do notinclude a sealant dispenser 305, and sealant device 306 contains onemore laser devices. Such resealing is performed, for example, inaccordance with the teachings of any of the following patents and patentapplications, each of which is hereby expressly incorporated byreference in its entirety as part of the present disclosure: U.S. patentapplication Ser. No. 12/254,789, filed Oct. 20, 2008, entitled“Container Having a Closure and Removable Resealable Stopper for Sealinga Substance Therein and Related Method,” which, in turn, claims thebenefit of U.S. Patent Application Ser. No. 60/981,107, filed Oct. 18,2007, entitled “Container Having a Closure and Removable ResealableStopper for Sealing a Substance Therein;” U.S. patent application Ser.No. 12/245,678, filed Oct. 3, 2008, entitled “Apparatus For Formulatingand Aseptically Filling Liquid Products,” and U.S. patent applicationSer. No. 12/245,681, filed Oct. 3, 2008, entitled “Method ForFormulating and Aseptically Filling Liquid Products,” which, in turn,claim the benefit of U.S. Patent Application Ser. No. 60/997,675, filedOct. 4, 2007, entitled “Apparatus and Method for Formulating andAseptically Filling Liquid Products;” U.S. patent application Ser. No.12/875,440, filed Sep. 3, 2010, entitled “Device with Needle Penetrableand Laser Resealable Portion and Related Method,” now U.S. Pat. No.7,980,276, which is a divisional of U.S. patent application Ser. No.12/371,386, filed Feb. 13, 2009, entitled “Device with Needle Penetrableand Laser Resealable Portion,” now U.S. Pat. No. 7,810,529, which is acontinuation of U.S. patent application Ser. No. 11/949,087, filed Dec.3, 2007, entitled “Device with Needle Penetrable and Laser ResealablePortion and Related Method,” now U.S. Pat. No. 7,490,639, which is acontinuation of similarly titled U.S. patent application Ser. No.11/879,485, filed Jul. 16, 2007, now U.S. Pat. No. 7,445,033, which is acontinuation of similarly titled U.S. patent application Ser. No.11/408,704, filed Apr. 21, 2006, now U.S. Pat. No. 7,243,689, which is acontinuation of U.S. patent application Ser. No. 10/766,172, filed Jan.28, 2004, entitled “Medicament Vial Having a Heat-Sealable Cap, andApparatus and Method for Filling the Vial,” now U.S. Pat. No. 7,032,631,which is a continuation-in-part of similarly titled U.S. patentapplication Ser. No. 10/694,364, filed Oct. 27, 2003, now U.S. Pat. No.6,805,170 which is a continuation of similarly titled U.S. patentapplication Ser. No. 10/393,966, filed Mar. 21, 2003, now U.S. Pat. No.6,684,916, which is a divisional of similarly titled U.S. patentapplication Ser. No. 09/781,846, filed Feb. 12, 2001, now U.S. Pat. No.6,604,561, which, in turn, claims the benefit of similarly titled U.S.Provisional Patent Application Ser. No. 60/182,139, filed Feb. 11, 2000,and similarly titled U.S. Provisional Patent Application Ser. No.60/443,526, filed Jan. 28, 2003, and similarly titled U.S. ProvisionalPatent Application Ser. No. 60/484,204, filed Jun. 30, 2003; U.S. patentapplication Ser. No. 13/193,662, filed Jul. 29, 2011, entitled “SealedContained and Method of Filling and Resealing Same,” which is acontinuation of U.S. patent application Ser. No. 12/791,629, filed Jun.1, 2010, entitled “Sealed Containers and Methods of Making and FillingSame,” now U.S. Pat. No. 7,992,597, which is a divisional of U.S. patentapplication Ser. No. 11/515,162, filed Sep. 1, 2006, entitled “SealedContainers and Methods of Making and Filling Same,” now U.S. Pat. No.7,726,352, which is a continuation of U.S. patent application Ser. No.10/655,455, filed Sep. 3, 2003, entitled “Sealed Containers and Methodsof Making and Filling Same,” now U.S. Pat. No. 7,100,646, which is acontinuation-in-part of U.S. patent application Ser. No. 10/393,966,filed Mar. 21, 2003, entitled “Medicament Vial Having A Heat-SealableCap, and Apparatus and Method For Filling The Vial,” now U.S. Pat. No.6,684,916, which is a divisional of similarly titled U.S. patentapplication Ser. No. 09/781,846, filed Feb. 12, 2001, now U.S. Pat. No.6,604,561, which, in turn, claims the benefit of similarly titled U.S.Provisional Patent Application Ser. No. 60/182,139, filed on Feb. 11,2000, and U.S. Provisional Patent Application Ser. No. 60/408,068, filedSep. 3, 2002, entitled “Sealed Containers and Methods Of Making andFilling Same;” U.S. patent application Ser. No. 12/627,655, filed Nov.30, 2009, entitled “Adjustable Needle Filling and Laser SealingApparatus and Method,” now U.S. Pat. No. 8,096,333, which is acontinuation of similarly titled U.S. patent application Ser. No.10/983,178, filed Nov. 5, 2004, which, in turn, claims the benefit ofU.S. Provisional Patent Application Ser. No. 60/518,267, filed Nov. 7,2003, entitled “Needle Filling and Laser Sealing Station,” and similarlytitled U.S. Provisional Patent Application Ser. No. 60/518,685, filedNov. 10, 2003; U.S. patent application Ser. No. 11/901,467, filed Sep.17, 2007 entitled “Apparatus and Method for Needle Filling and LaserResealing,” which is a continuation of similarly titled U.S. patentapplication Ser. No. 11/510,961 filed Aug. 28, 2006, now U.S. Pat. No.7,270,158, which is a continuation of similarly titled U.S. patentapplication Ser. No. 11/070,440, filed Mar. 2, 2005; now U.S. Pat. No.7,096,896, which, in turn, claims the benefit of U.S. Provisional PatentApplication Ser. No. 60/550,805, filed Mar. 5, 2004, entitled ‘Apparatusfor Needle Filling and Laser Resealing;” U.S. patent application Ser.No. 12/768,885, filed Apr. 28, 2010, entitled “Apparatus for Molding andAssembling Containers with Stoppers and Filling Same,” now U.S. Pat. No.7,975,453, which is a continuation of similarly titled U.S. patentapplication Ser. No. 11/074,513, filed Mar. 7, 2005, now U.S. Pat. No.7,707,807, which claims the benefit of U.S. Provisional PatentApplication Ser. No. 60/551,565, filed Mar. 8, 2004, entitled “Apparatusand Method For Molding and Assembling Containers With Stoppers andFilling Same;” U.S. patent application Ser. No. 12/715,821, filed Mar.2, 2010, entitled “Method for Molding and Assembling Containers withStopper and Filling Same,” which is a continuation of similarly titledU.S. patent application Ser. No. 11/074,454, filed Mar. 7, 2005, nowU.S. Pat. No. 7,669,390; U.S. patent application Ser. No. 11/339,966,filed Jan. 25, 2006, entitled “Container Closure With Overlying NeedlePenetrable and Thermally Resealable Portion and Underlying PortionCompatible With Fat Containing Liquid Product, and Related Method,” nowU.S. Pat. No. 7,954,521, which, in turn, claims the benefit of U.S.Provisional patent application Ser. No. 60/647,049, filed Jan. 25, 2005,entitled “Container with Needle Penetrable and Thermally ResealableStopper, Snap-Ring, and Cap for Securing Stopper;” U.S. patentapplication Ser. No. 12/861,354, filed Aug. 23, 2010, entitled “Ready ToDrink Container With Nipple and Needle Penetrable and Laser ResealablePortion, and Related Method;” which is a divisional of similarly titledU.S. patent application Ser. No. 11/786,206, filed Apr. 10, 2007, nowU.S. Pat. No. 7,780,023, which, into turn, claims the benefit ofsimilarly titled U.S. Provisional Patent Application Ser. No.60/790,684, filed Apr. 10, 2006; U.S. patent application Ser. No.11/295,251, filed Dec. 5, 2005, entitled “One-Way Valve, Apparatus andMethod of Using the Valve,” now U.S. Pat. No. 7,322,491, which, in turn,claims the benefit of similarly titled U.S. Provisional PatentApplication Ser. No. 60/644,130, filed Jan. 14, 2005, and similarlytitled U.S. Provisional Patent Application Ser. No. 60/633,332, filedDec. 4, 2004; U.S. patent application Ser. No. 12/789,565, filed May 28,2010, entitled “Resealable Containers and Methods of Making, Filling andResealing the Same,” which is a continuation of U.S. patent applicationSer. No. 11/933,272, filed Oct. 31, 2007, entitled “ResealableContainers and Assemblies for Filling and Resealing Same,” now U.S. Pat.No. 7,726,357, which is a continuation of U.S. patent application Ser.No. 11/515,162, filed Sep. 1, 2006, entitled “Sealed Containers andMethods of Making and Filling Same,” now U.S. Pat. No. 7,726,352; U.S.patent application Ser. No. 13/045,655, filed Mar. 11, 2011, entitled“Sterile Filling Machine Having Filling Station and E-Beam Chamber,”which is a continuation of U.S. patent application Ser. No. 12/496,985,filed Jul. 2, 2009, entitled “Sterile Filling Machine Having NeedleFilling Station and Conveyor,” now U.S. Pat. No. 7,905,257, which is acontinuation of U.S. patent application Ser. No. 11/527,775, filed Sep.25, 2006, entitled “Sterile Filling Machine Having Needle FillingStation within E-Beam Chamber,” now U.S. Pat. No. 7,556,066, which is acontinuation of similarly titled U.S. patent application Ser. No.11/103,803, filed Apr. 11, 2005, now U.S. Pat. No. 7,111,649, which is acontinuation of similarly titled U.S. patent application Ser. No.10/600,525, filed Jun. 19, 2003, now U.S. Pat. No. 6,929,040, which, inturn, claims the benefit of similarly-titled U.S. Provisional PatentApplication Ser. No. 60/390,212, filed Jun. 19, 2002; U.S. patentapplication Ser. No. 13/326,177, filed Dec. 14, 2011, entitled “Devicewith Penetrable and Resealable Portion and Related Method,” which is acontinuation of similarly titled U.S. patent application Ser. No.13/170,613, filed Jun. 28, 2011, which is a continuation of U.S. patentapplication Ser. No. 12/401,567, filed Mar. 10, 2009, entitled “Devicewith Needle Penetrable and Laser Resealable Portion and Related Method,”now U.S. Pat. No. 7,967,034, which is a continuation of similarly titledU.S. patent application Ser. No. 11/933,300, filed Oct. 31, 2007, nowU.S. Pat. No. 7,500,498; U.S. patent application Ser. No. 13/329,483,filed Apr. 30, 2011, entitled “Ready to Feed Container,” which is acontinuation of International Application Serial No. PCT/US2011/034703,filed Apr. 30, 2011, entitled “Ready to Feed Container and Method,”which, in turn, claims the benefit of U.S. Provisional PatentApplication Ser. No. 61/330,263 filed Apr. 30, 2010; and U.S.Provisional Patent Application Ser. No. 61/476,523, filed Apr. 18, 2011,entitled “Filling Needle and Method.”

In other embodiments, the heat-sealable septum is sealed by contactingthe septum with a heated probe, as disclosed, for example, in U.S. Pat.No. 6,604,561, issued Aug. 12, 2003, entitled “Medicament Vial Having aHeat-Sealable Cap, and Apparatus and Method for Filling the Vial,”and/or a liquid sealing process as disclosed in co-pending U.S. patentapplication Ser. No. 13/745,721, filed Jan. 18, 2013, entitled “Devicewith Co-Molded Closure, One-Way Valve, Variable-Volume Storage Chamberand Anti-Spritz Feature and Related Method,” which is hereby expresslyincorporated by reference in its entirety as part of the presentdisclosure.

Once the container 301 is filled and resealed, the conveyor mechanismfor the support 302 reverses direction (from left to right in FIG. 20),and conveys the filled and sealed container out of the processing space310 in the position shown in FIGS. 20 and 21, so that a user can accessthe filled container 301 and remove it from the support 302. Inalternative embodiments, the door 308 is opened and the sealed, filledcontainer 301 is removed from the support 302 and apparatus 300 at theresealing station. Alternatively still, the apparatus has an opening onthe end of the processing space 310 adjacent to the resealing stationthrough which the container 301 is conveyed out of the processing space310 or otherwise provides access to the filled container 301 forremoval.

As noted above, apparatus 300 in different embodiments is manually orautomatically operated. The control panel 315 includes a power switch,an ON/OFF operation switch, and is in operative communication withcomputerized systems that include software and/or programming to be usedto control the amount and flow of substance, sealant, and/or sterilantused during the operation of apparatus 300, and also control the fluidflow of substance through and from the filling device 304. Further, thecontrol panel 315 can be used to select from different types ofsubstances, sealants, and/or sterilants, depending on the configurationof the substance supply and the needs of the user. As discussed above,the control panel 315 may control the movement of the support 302, andthus the container 301 to be filled, through the apparatus 300, whichcontrol may be automatic via one or more selectable programs installedin the apparatus, or via instruction of the operator as entered throughthe control panel 315.

Furthermore, as noted, control panel 315 is connected to otherelectrical components within apparatus 300, such as motors, processors,heaters, etc. To maintain the proper operating conditions for theseelectrical components, apparatus 300 includes an exhaust fan 313 on thetop thereof that draws cooling air into and through the apparatus 300and over the components, preventing overheating. Alternatively, theexhaust fan 313 is positioned on a side or back of the apparatus 300.Additionally, the electrical components of apparatus 300 are modularlyinstalled therein, such that easy maintenance and exchange of separateelectrical parts is possible as needed. For example, the electricalcontrol for the sanitizing device 303 and the electrical control for thefilling device 304 are located in separate modules or separateelectrical panels, such that one can be replaced without affecting theother.

The apparatus 300 provides a process of filling and sealing a singlecontainer 301 at a time, in a continuous process, allowing foruser-controlled, on-demand sequential filling of containers.Accordingly, after removal of the filled and sealed container 301,another (sealed) empty container 301 can be mounted on the support 302and the above filling process repeated. During this operation, thefilling device 304 is reused for subsequent fillings. This operation canbe used for multiple container fillings, without changing the fillingdevice 304.

However, if there is a need to change the filling device 304, forexample due to a change in the substance to be dispensed therethrough orfor any other reason, the filling device 304 can be removed andreplaced. To do so, the cap 311 is replaced onto the needle 304. In thisprocess, a user uses the control panel 315 to initiate this process. Ineffect, the reverse of the process to remove the cap 311 is performed.

As seen in FIG. 20, the cap 311 has been held in the cap grip 319 duringthe filling process. The support 302 is moved into the processing space310 until aligned directly underneath the filling device 304. Thefilling device 304 is then moved downward until the cap 311 engages ontothe filing device 304, e.g., snaps on, and the filling device isretracted to remove the cap up out of the cap grip 319.

In embodiments where the cap 311 is held in the storage position in thecap holder 312 throughout the filling and sealing process, cap 311 isremoved from the cap holder 312 by moving the cap grip 319 intoalignment underneath cap holder 312, the cap holder 312 is moveddownward until the cap 311 engages and is retained by the cap grip 319,and the cap holder 312 is retracted upward, disengaging the cap 311 fromthe cap support 302. Next, the support 302 moves so that the cap 311 ispositioned and aligned with the filling device 304. Filling device 304is then lowered downward into the cap 311, engaging therewith, e.g.,snapping on, and retracted upward with the cap secured thereto and clearof the cap grip 319. The support 302 is then moved to the position shownin FIG. 20 so that a user can remove and/or exchange the filling device304.

The re-capping procedure is also performed when filling is complete, andbefore the apparatus 300 is shut down so that the filling device 304 iscapped during periods of non-use. Advantageously, this process can befully automated such that a user does not have to interact with anexposed portion of the filling device 304, such as the point of aneedle, and thus sanitary and safe conditions can be maintained.

Turning now to FIGS. 22-23, FIG. 22 partially illustrates the interiorof the apparatus 300, including electrical and mechanical components 335for the sanitizing station, electrical and mechanical components 336 forthe filling station, and electrical and mechanical components 337 forthe sealing station, each of which can be controlled by control panel315.

FIG. 23 shows additional detail of the control panel 315, which includesa touchscreen display 316, and buttons 317 to control operation ofapparatus 300. Control panel 315 in other embodiments includes analogcontrols, e.g., dials, switches, etc. In certain embodiments, thedisplay 315 is a dynamic touch-screen that provides easy step-by-stepoperating instructions to guide an operator through the filling process,thereby reducing training time. Furthermore, the operating software forthe apparatus 300 includes redundant safety measures to prevent and/orminimize malfunction and/or user error.

Apparatus 300, as described above, provides a filling process of acontainer with non-preserved (or, if desired, preserved) formulations inclosed containers in a non-classified environment, and sealing thereof.Advantageously, this is as safe as accepted aseptic filling methods ofpreserved or unpreserved formulations in open containers in a controlledenvironment. Furthermore, the apparatus 300 is a compact apparatus thatenables localized sterile filling on location. Because apparatus 300provides sanitization within the apparatus 300, no clean room isnecessary for filling containers 301.

Turning now to FIG. 24, an alternative embodiment of a filling andsealing apparatus 400 is shown. Apparatus 400 is substantially similarto apparatus 300, and similar reference numbers are used for similarcomponents and features, except preceded by the number “4” instead ofthe number “3.” Accordingly, apparatus 400 is shown with a container 401held by a support 402 that is conveyed through a processing space 410including a door 408. Apparatus 400 includes a control panel 415, asanitizing station including a sanitizing device 403, and a sealingstation including a sealant dispenser 405 and a sealer device 406. Asshown, apparatus 400, in contrast to apparatus 300, the cap holder 412and the filling device 404 are switched in position, such that the capholder 412 is adjacent to the sanitizing station, but the operation andmethod of filling and sealing of the container 401 is substantially thesame as described above with respect to apparatus 300.

As shown in FIG. 24, the apparatus 400 is supplied with substance forfilling into container 401 from one or more fluid sources and/orreservoirs that are separate from the apparatus 400. A substance supply440, such as a disposable bag, pouch, or other type of container, issupported on a rack or carousel 441, which in some embodiments rotatesand/or spins. The supply 440 is fluidly connected to apparatus 400, andthus filling device(s) 404, by a fluid line 442. The substance supply440 is, in some embodiments, a sterile, hermetically sealed containerthat contains a sterile, non-preserved substance to be dispensed intocontainer 401.

As noted, the substance supply 440 is fluidly connected to the apparatus400 by the fluid line 442. The fluid line 442 contains a sterileconnector 451, as discussed above, that permits the supply 440 to beconnected to the apparatus 400 and formed from a sterile fluid path forthe substance between the supply 440 and the apparatus 400. Thus, anentirely sterile fluid path sealed from the ambient atmosphere ismaintained during the filling process from the substance supply 440,into the apparatus 400, through the filling device 404 and into thesealed chamber of the container. In other applications that do notutilize sterile substances or require sterile transfer or filling, theconnectors need not be sterile connectors.

Carousel 441 is configured to hold multiple substance supplies 440, eachconnectable to the apparatus 400 via a sterile connector 451, such thata user can easily change which substance supply 440 is connected toapparatus 400. As such, a user of apparatus 400 can provide multiplesupplies of the same substance, such that when one substance supply 440empties, the empty supply can be quickly disconnected, and a replacementsubstance supply 400 may be quickly connected to the apparatus 400 tocontinue filling containers 401. Alternatively, different substances maybe stored in difference substance supplies 440, such that a user canchange the substance to be dispensed into container 401 with ease.During changing of the substance supply 440, the sterile fluid pathway,i.e., fluid line 442, is provided via the sterile connectors 451, whichmaintain the fluid pathways in a sealed condition with respect to theambient atmosphere, even when the supply 440 is disconnected from theapparatus 400. Moreover, a change of substance supply 440 can berelatively quick, e.g., within a few minutes, by disconnecting thesubstance supply 440 from the fluid line 442 using a connector, and thenattaching a second substance supply 440 to the fluid line 442. However,each substance supply may hold a sufficient volume of substance to fillmultiple containers 401 without requiring changing the substance supply440 often.

Furthermore, although shown with only one substance supply 440 connectedto apparatus 400 with a single fluid line 442, apparatus 400 can beconfigurable to receive fluid from multiple substance supplies 440, andeach substance supply 440 can be connected to apparatus 400 by adifferent sterile fluid line 442 and to a different filling device 404,for example apparatus 400 can include two or more filling devices 404.Accordingly, mixing of substances within a container 401 is permitted bythe apparatus 400.

In this manner, it is possible to fill different substances into asingle container 401, thereby creating a formulation from multiplesubstances in the container 401. Such processes are described, forexample, in co-pending U.S. patent application Ser. No. 12/245,678,filed Oct. 3, 2008, entitled “Apparatus and Method for Formulating andAseptically Filling Liquid Products,” and U.S. patent application Ser.No. 12/245,681, filed Oct. 3, 2008, entitled “Apparatus and Method forFormulating and Aseptically Filling Liquid Products,” which are herebyexpressly incorporated by reference in their entireties as part of thepresent disclosure. It is also possible to fill different containers 401with different substances easily. Accordingly, several differentsubstances may be held on the carousel 441, and used as desired over thecourse of time to fill the particular substance desired on demand.

Alternatively, although shown as a rack or carousel 441, one or morefluid supplies may be housed in a separate storage container, device, ortank that can control and maintain appropriate temperatures, humiditylevels, light levels, etc., such that any substances stored therein arenot damaged while in a storage state. Such a storage container may beconfigured with one or more fluid lines that can fluidly communicatesubstance from the storage container to the apparatus 400 for fillingcontainers 401. Furthermore, although shown with the substance supply440 separate from the apparatus 400, the apparatus 400 can beconfigurable to house one or more substance supplies within theapparatus 400.

Turning now to FIG. 25, an alternative configuration of an apparatus 500and carousel 541 is shown. The apparatus 500 and carousel 541, and othercomponents shown therein, are substantially similar to the apparatus 400and carousel 441 of FIG. 24, and like elements are similarly labeled,except preceded by the number “5” instead of “4.” Apparatus 500 includesa control panel 515, and a processing space 510 including a sterilizingdevice 503, a filling device 504, a sealant dispenser 505, and a sealerdevice 506, housed within the processing space 510 including a door 508.The container 501 is held by support 502 which conveys the container 501through the processing space 510 to fill and seal container 501, asdescribed above. As shown, apparatus 500 is fluidly connected to asubstance supply 540 by a fluid line 542 via a sterile connector 551,which is retained on a carousel 541. As shown, the carousel 541 isconfigured to support multiple substance supplies 540, and the substancesupplies 540 may be fluidly connected to apparatus 500, and one or morefilling devices 504, by one or more fluid lines 542, in a similar manneras described above with respect to apparatus 400.

Though the apparatuses 300, 400, 500 can be used to fill variouscontainers or devices as describe above, other filling apparatuses maybe employed, including that disclosed in co-pending U.S. patentapplication Ser. No. 13/861,502, filed Apr. 12, 2013, entitled “ModularFilling Apparatus and Method,” which claims the benefit of similarlytitled U.S. Provisional Patent Application No. 61/686,867, filed Apr.13, 2012, each of which is hereby expressly incorporated by reference inits entirety as part of the present disclosure.

Advantageously, embodiments of the apparatuses disclosed herein can usedin any setting where, e.g., small-scale sterile filling is desired, suchas a laboratory setting with a desk-top apparatus. The apparatus issmall and compact, and easily fits on a typical desk or bench top, andis easily moved and/or transported. Some embodiments of the apparatusare compact enough to fit within a carry-case or suitcase. Variousembodiments are less than about 2 cubic feet (75 dm³) in volume andweigh less than about 42 pounds (19 kg). Accordingly, the apparatus canbe easily transferred from one location to another. In addition, theabove-described apparatuses are user-friendly devices providing aturnkey sterile filling system. There is only a single electricalconnection, and the apparatus is fully integrated to perform all thefunctions described above, without human interaction and/or humancontamination. There is no need for vaporized hydrogen peroxide (VHP) orother fluid sterilant system, compressed air, filtered or sterilelaminar flow environments, or any complex or costly isolators, thoughthe apparatus in some embodiments could include a VHP supply forsanitation.

Turning now to FIG. 26, a schematic depiction is shown of an apparatus,as described above, as used in a hospital setting, connecting anapparatus 600 providing a closed sterile fluid path 643 to a patient699. As shown, patient 699 lies on a bed 698 in a patient care room.Apparatus 600, similar to apparatus 300, 400, and 500, described above,may be placed in a patient room on a table next to the patient 699, ormay be placed in a different roon and the filled, sealed containertransported to the patient 699 room. A substance supply 640, held on acarousel 641, provides a supply of substance to apparatus 600 by asterile fluid line 642. As shown, a tank 650 is also provided with alarger supply of substance, and is connected to the substance supply 641by another sterile fluid line 642. Sterile connectors 651, such as thosedescribed above, may form part of the sterile fluid lines 642. In suchmanner, multiple substance containers can be connected to the apparatus600, such that multiple substances can be selectively delivered to apatient, or different substances delivered to different patients.

To provide the patient with the substance from apparatus 600, theapparatus 600 is in sterile fluid communication with a patient throughan IV or similar sterile fluid connector 643. In such embodiments,instead of the apparatus 600 delivering substance to a filling member topenetrate a container, the apparatus 600 delivers substance to the IVline. The sterile fluid line between the apparatus 600 and the patient699 includes a sterile connector 651, as described above, so that the IVline can be disconnected from the apparatus while maintaining a sterile,sealed fluid path through the apparatus 600. Furthermore, an additionalperistaltic pump 652 between the apparatus 600 and the patient 699allows the fluid flow injection and supply to the patient can beprecisely controlled by a patient care specialist.

The ability to disconnect the patient IV line from the apparatus andmaintain a sterile fluid path, i.e., via sterile connector 651, alongwith the small and portable nature of the apparatus 600 as discussedabove, allows the apparatus 600 to be moved from one patient treatmentroom to another to treat different patients. This advantageously avoidsneeding to move the patient to another location to administer thetreatment, which might be medically detrimental to the patient. Inaddition, the above-described ability to quickly connect and disconnectone or more different substance supplies to the apparatus 600 permits a“standard” set of substances to be maintained with the apparatus fordifferent treatments, and also, to replace substance supplies as neededwith minimal downtime of the apparatus or disruption to patienttreatments. Yet further, the apparatus 600 allows multiple dosing of apatient over time, where between such doses the IV line is disconnectedfrom the apparatus via sterile connector 651, for patient comfort,mobility, or infusion of alternative substances, without compromisingthe sterile fluid pathway for subsequent doses.

In alternative embodiments, apparatus 600 is configured to fillcontainers, as described above, such as IV bags, which are then providedfor patient use immediately and on-site in the patient's care room. Assuch, specific care defined IV bags may be filled in a patient careroom, allowing for on-site, immediate response to needs of the patient.

Advantageously, a completely sterile delivery, from an originalsubstance source to application to a patient is provided, wherein thesubstance is maintained sterile, and sealed with respective to ambientatmosphere, from the substance source, through sterile filling into acontainer or other device for patient delivery and, in turn, deliveryfrom such container or device to a patient. For example, with referenceto FIG. 26, in an alternative embodiment, substance source 640 is asterile filled and enclosed substance source, such as a pouch, thatincludes a sterile connector for attachment to a sterile fluid line, forexample the sterile connectors described and incorporated by referenceabove. The sterile connector of the substance source 640 is connected toa sterile fluid line 642 that is fluidly connected to the closed needleof the apparatus 600 (i.e., the sterile connector, flexible fluid lineengageable by, for example, a peristaltic pump, and closed needle form afilling kit that is mounted in the filling apparatus 600 for arespective sterile fill). The apparatus 600 then fills a sterilecontainer in accordance with the sterile filling and resealing processdescribed above with a substance to be administered to a patient. Thefilled, sterile container also includes a sterile connector, for examplethe sterile connectors described and incorporated by reference above,and is removed from the apparatus 600. The filled, sterile containerfilled by apparatus 600 is then connected through its sterile connectorto a sterile fluid line that is provided for delivery of the sterilefilled substance to a patient, for example, a catheter or IV line. Insuch embodiment, the catheter or IV line includes a catheter or needleon its end opposite the sterile connector connected to the sterilecontainer for delivery of the sterile filled substance to a patient.Accordingly, a completely closed, i.e., from the ambient atmosphere, andsterile process, from source to patient, is provided without risk ofcontamination of a sterile substance. Further, in some embodiments, aperistaltic pump is provided between the filled, sterile container andthe patient to provide a controlled application of the substance to thepatient. Moreover, advantageously, the substance source 640 and/or theapparatus 600 can easily and efficiently be changed when a differentpatient and/or different formulation of substance is to be used.

As may be recognized by those of ordinary skill in the pertinent artbased on the teachings herein, numerous changes and modifications may bemade to the above-described and other embodiments without departing fromits scope as defined in the claims. For example, the components of thevial or other device and the filling device may take any of numerousdifferent configurations, or may be made of any of numerous differentmaterials, that are currently known, or that later become known. Forexample, rather than taking the form of a needle, the filling orinjection member could take the form of a cannula. The device to befilled, on the other hand, could include a one-way filling valve, and anelastic septum that receives the filling cannula, forms an annularinterface with the filling cannula, and decontaminates the fillingcannula prior to opening the shutter or other enclosure on the cannula,engaging the one-way valve, and filling the sterile chamber of a device.The filling devices likewise may be employed in any of numerousdifferent configurations, driven into and out of engagement with thedevices to be filled in any of numerous different ways, and the filleddevices may be transported on any of numerous different types ofconveyors or in other ways. Similarly, the devices to be filled may takethe form of any of numerous different containers or devices that arecurrently known, or that later become known, such as vials, pouches,tubes, syringes, single dose delivery devices and multiple dose deliverydevices. Also, the filling device may be used to inject any of numerousdifferent types of fluids or other substances into the vial or otherdevice for any of numerous different applications, including, forexample, medicaments, pharmaceuticals, vaccines, liquid nutritionproducts, supplements, and numerous other products that are currentlyknown, or that later become known. In addition, the filling process maytake place in any of numerous different types of ambient environmentsdefining any of numerous different types of contamination or sterilityassurance levels. Accordingly, this detailed description of embodimentsis to be taken in an illustrative, as opposed to a limiting sense.

1. A method, comprising the following steps: (a) penetrating an elasticseptum of a device with an injection member, wherein the device definesa sealed, empty, sterile chamber in fluid communication with the elasticseptum; (b) during the penetrating step, forming an annular interfacebetween the elastic septum and the injection member extending axiallybetween a penetration point on an interior surface of the elastic septumin fluid communication with the sterile chamber, and an exterior surfaceof the septum engaging the injection member, and de-contaminating theinjection member by at least one of (i) friction between the elasticseptum and injection member at the annular interface, and (ii)elongation of the elastic septum at the annular interface; (c)introducing a substance through the injection member and into thesterile chamber of the device; (d) withdrawing the injection member fromthe elastic septum; (e) allowing the elastic septum to reseal itself ata penetration aperture resulting from withdrawal of the injectionmember; and (f) maintaining the chamber sterile throughout steps (a)through (e).
 2. (canceled)
 3. (canceled)
 4. A method as defined in claim1, further comprising performing the penetrating step in an ambientenvironment defining a level of contamination greater than about class100 or ISO 5 and less than or equal to about class 100,000 or ISO
 8. 5.A method as defined in claim 1, wherein the de-contaminating of theinjection member includes achieving at least approximately a 3 logreduction in bio-burden at the annular interface between the elasticseptum and injection member.
 6. (canceled)
 7. A method as defined inclaim 5, wherein the de-contaminating of the injection member includesachieving at least approximately a 6 log reduction in bio-burden at theannular interface between the elastic septum and injection member. 8.(canceled)
 9. (canceled)
 10. (canceled)
 11. A method as defined in claim1, wherein the elastic septum includes a penetration zone defining anapproximate dome-shape, and the penetration step includes penetratingthe elastic septum in the dome-shaped penetration zone.
 12. A method asdefined in claim 11, wherein the elastic septum defines a substantiallyconvex exterior surface, and a substantially concave interior surfaceopposite the convex exterior surface.
 13. A method as defined in claim12, wherein the interior surface of the septum defines a relativelyrecessed surface extending substantially about the penetration zone. 14.A method as defined in claim 13, wherein the relatively recessed surfaceis a groove.
 15. A method as defined in claim 14, further comprisingduring the penetrating step reducing the strain on the interior surfaceof the septum within the penetration zone with the groove. 16.(canceled)
 17. A method as defined in claim 1, wherein the elasticseptum defines a hardness within the range of about 20 to about 80 shoreA.
 18. A method as defined in claim 1, wherein elastic septum defines apenetration zone that is penetrated by the injection member, and thepenetration zone is shaped to enhance the pressure exerted by theelastic septum onto the injection member during the penetrating step.19. (canceled)
 20. (canceled)
 21. A method as defined in claim 1,wherein during the penetrating step, the internal surface of the elasticseptum forms an initial crack at substantially the maximum elongation ofthe elastic septum by the injection member.
 22. A method as defined inclaim 1, wherein the annular interface is defined by a portion of thepenetrated elastic septum extending annularly about the injection membersubstantially throughout an axial distance extending between theinterior and exterior points of contact between the penetrated septumand injection member of at least about ½ mm.
 23. (canceled) 24.(canceled)
 25. (canceled)
 26. A method as defined in claim 1, whereinduring the penetrating step, the annular interface between the elasticseptum and injection member defines a substantially inverted,frusto-conical shape.
 27. A method as defined in claim 1, wherein thecoefficient of friction of the septum-engaging surface of the injectionmember is less than the coefficient of friction of the penetratedportion of the elastic septum.
 28. (canceled)
 29. (canceled) 30.(canceled)
 31. (canceled)
 32. (canceled)
 33. (canceled)
 34. (canceled)35. (canceled)
 36. (canceled)
 37. (canceled)
 38. (canceled)
 39. A methodas defined in claim 1, wherein the injection member includes at leastone port for dispensing the substance from the injection member, and themethod further includes sealing the port with respect to the ambientatmosphere until at least a portion of the port is in fluidcommunication with the sterile chamber, and further comprisingintroducing a toxic substance through the injection member and into thesterile chamber of the device, and using the closure to prevent anyexposure of the toxic substance to the ambient atmosphere throughoutsteps a) through e).
 40. A method as defined in claim 1, wherein thede-contaminating of the injection member includes exerting pressure withthe elastic septum onto the injection member at the annular interfacebetween the elastic septum and injection member and, in turn, killingorganisms at the interface.
 41. (canceled)
 42. A method as defined inclaim 1, wherein the elastic septum defines a penetration zone that ispenetrated by the injection member, and the penetration zone of theelastic septum defines a thickness prior to penetration within the rangeof about ½ to about two times an outer diameter of the injection member.43. A method as defined in claim 1, wherein the elastic septum defines apenetration zone including a recess defining a reduced thickness of theelastic septum, and the penetrating step includes penetrating theelastic septum at the reduced thickness of the penetration zone.
 44. Amethod as defined in claim 43, wherein the penetration zone recessdefines a substantially frusto-conical shape.
 45. A method as defined inclaim 43, wherein the injection member includes a penetrating tipdefining a first included angle, and the penetration zone recess definesa second included angle that is substantially the same as the firstincluded angle.
 46. (canceled)
 47. (canceled)
 48. (canceled)
 49. Adevice that is sterile fillable by an injection member defining a portthat is normally sealed with respect to ambient atmosphere and can beopened to dispense substance from the injection member therethrough,wherein the device comprises: a body defining a sealed, empty, sterilechamber; and an elastic septum in fluid communication with the sealed,empty, sterile chamber, wherein (A) the elastic septum is penetrable bythe injection member and forms an annular interface between the elasticseptum and the injection member extending axially between (i) apenetration point on an interior surface of the elastic septum in fluidcommunication with the sterile chamber, and (ii) an exterior surface ofthe septum engaging the injection member, and (B) relative movement ofthe injection member and elastic septum de-contaminates the injectionmember through at least one of (i) friction between the elastic septumand injection member at the annular interface, and (ii) elongation ofthe elastic septum at the annular interface.
 50. A device as defined inclaim 49, wherein relative movement of the injection member and elasticseptum opens the port of the injection member after decontaminating theinjection member at the annular interface and at least part of the portis passed through the septum, and opens the port of the injection memberinto fluid communication with the sterile chamber to dispense substancefrom the injection member into the sterile chamber.
 51. (canceled)
 52. Adevice as defined in claim 49, wherein the relative movement of theinjection member and elastic septum de-contaminates the injection memberby at least approximately a 3 log reduction in bio-burden at the annularinterface between the elastic septum and injection member. 53.(canceled)
 54. A device as defined in claim 52, wherein the relativemovement of the injection member and elastic septum de-contaminates theinjection member by at least approximately a 6 log reduction inbio-burden at the annular interface between the elastic septum andinjection member.
 55. (canceled)
 56. (canceled)
 57. A device as definedin claim 49, wherein the elastic septum includes a penetration zonepenetrable by the injection member and defining an approximatedome-shape.
 58. A device as defined in claim 57, wherein the elasticseptum defines a substantially convex exterior surface, and asubstantially concave interior surface opposite the convex exteriorsurface.
 59. A device as defined in claim 58, wherein the interiorsurface of the septum defines a relatively recessed surface extendingsubstantially about the penetration zone.
 60. A device as defined inclaim 59, wherein the relatively recessed surface is a groove.
 61. Adevice as defined in claim 49, further including means for reducing thestrain on an interior surface of the septum during penetration thereofby the injection member.
 62. (canceled)
 63. (canceled)
 64. A device asdefined in claim 49, wherein the elastic septum defines a hardnesswithin the range of about 20 to about 80 shore A.
 65. A device asdefined in claim 49, wherein elastic septum defines a penetration zonethat is penetrable by the injection member, and the penetration zone isshaped to enhance the pressure exerted by the elastic septum onto theinjection member during penetration thereof by the injection member. 66.(canceled)
 67. (canceled)
 68. A device as defined in claim 49, whereinthe annular interface is defined by a portion of the penetrated elasticseptum extending annularly about the injection member substantiallythroughout an axial distance extending between interior and exteriorpoints of contact between the penetrated septum and injection member ofat least about ½ mm.
 69. (canceled)
 70. (canceled)
 71. (canceled)
 72. Adevice as defined in claim 49, wherein the annular interface between theelastic septum and injection member defines a substantially inverted,frusto-conical shape.
 73. A device as defined in claim 49, wherein thecoefficient of friction of the penetrated portion of the elastic septumis greater than the coefficient of friction of the septum-engagingsurface of the injection member.
 74. (canceled)
 75. (canceled) 76.(canceled)
 77. (canceled)
 78. A device as defined in claim 49, whereinthe elastic septum is configured to exert pressure onto the injectionmember at the annular interface between the elastic septum and injectionmember to thereby kill organisms at the interface.
 79. (canceled)
 80. Adevice as defined in claim 49, wherein the elastic septum defines apenetration zone that is penetrated by the injection member, and thepenetration zone of the elastic septum defines a thickness prior topenetration within the range of about ½ to about two times an outerdiameter of the injection member.
 81. A device as defined in claim 49,wherein the elastic septum defines a penetration zone including a recessdefining a reduced thickness of the elastic septum that is penetrated bythe injection member.
 82. A device as defined in claim 81, wherein thepenetration zone recess defines a substantially frusto-conical shape.83. A device as defined in claim 81, wherein the injection memberincludes a penetrating tip defining a first included angle, and thepenetration zone recess defines a second included angle that issubstantially the same as or greater than the first included angle. 84.(canceled)
 85. A device as defined in claim 49 in combination with afilling device including an injection member defining a port that isnormally sealed with respect to ambient atmosphere and can be opened todispense substance from the injection member therethrough.
 86. A devicethat is sterile filled by an injection member including means forsealing the interior of the injection member with respect to ambientatmosphere and for opening to dispense substance from the injectionmember therethrough, wherein the device comprises: first means defininga sealed, empty, sterile chamber; and second means in fluidcommunication with sealed, empty, sterile chamber that is penetrable bythe injection member (A) for forming an annular interface between theelastic septum and the injection member extending axially between (i) apenetration point on an interior surface of the second means in fluidcommunication with the sterile chamber, and (ii) an exterior surface ofthe second means engaging the injection member, and (B) forde-contaminating the injection member through at least one of (i)friction between the second means and injection member at the annularinterface, and (ii) elongation of the second means at the annularinterface.
 87. (canceled)
 88. An apparatus comprising: a housing atleast partially defining a processing space; a device support forreleasably holding a sealed device defining a sealed chamber for storinga substance therein, and a penetrable portion in fluid communicationwith the chamber and penetrable by a filling or injection member; aconveyor defining a path for transporting the support and the devicealong the path and through the processing space; and within theprocessing space: a de-contamination station located on the conveyorpath and configured to de-contaminate at least the penetrable surface ofthe penetrable septum; a filling station located on the conveyor pathdownstream of the de-contamination station and including at least onefilling or injection member coupled or connectible in fluidcommunication with a source of substance to be filled into the chamberof the device, wherein at least one of the filling or injection memberand the device is movable relative to the other within the fillingstation to penetrate the penetrable septum with the filling or injectionmember, introduce substance through the filling or injection member andinto the chamber, and withdraw the filling or injection member from theseptum; a resealing station located on the conveyor path downstream ofthe filling station configured to reseal an aperture formed in theseptum during the filling of the chamber of the device at the fillingstation; and a cap storage station configured for storing a cap removedfrom the filling or injection member during filling and resealing of thedevice.
 89. An apparatus as defined in claim 88, further comprising acap removal device configured to remove the cap from the filling orinjection member prior to filling of the device, store the cap in a capstorage station, retrieve the cap from the storage station after fillingand resealing of the device, and reapply the cap to the filling orinjection member.
 90. An apparatus comprising: a housing at leastpartially defining a processing space; a device support for releasablyholding a sealed device defining a sealed chamber for storing asubstance therein, and a penetrable portion in fluid communication withthe chamber and penetrable by a filling or injection member; a conveyordefining a path for transporting the support and the device along thepath and through the processing space; and within the processing space:a de-contamination station located on the conveyor path and configuredto de-contaminate at least the penetrable surface of the penetrableseptum; a filling station located on the conveyor path downstream of thede-contamination station and including at least one filling or injectionmember coupled or connectible in fluid communication with a source ofsubstance to be filled into the chamber of the device, wherein at leastone of the filling or injection member and the device is movablerelative to the other within the filling station to penetrate thepenetrable septum with the filling or injection member, introducesubstance through the filling or injection member and into the chamber,and withdraw the filling or injection member from the septum; aresealing station located on the conveyor path downstream of the fillingstation configured to reseal an aperture formed in the septum during thefilling of the chamber of the device at the filling station; and asource of substance placeable into and removable from fluidcommunication with the filling station by a sterile connector that isconfigured to provide a fluid flow path between the source of substanceand the filling station that is sealed from the ambient atmosphere whenthe source of substance is placed into fluid communication with thefilling station and maintains the fluid flow path sealed from theambient atmosphere when the source of substance is not in fluidcommunication with the filling station.
 91. (canceled)
 92. An apparatusas defined in claim 90, wherein the source of substance comprises one ormore substance supply containers each containing a different substanceor formula.
 93. (canceled)
 94. (canceled)
 95. A method comprising thefollowing step: (i) conveying a filling or injection member into afilling device, wherein the filling or injection member is housed withina cap and the filling device comprises: a housing at least partiallydefining a processing space; a device support for releasably holding asealed device defining a sealed chamber for storing a substance therein,and a penetrable portion in fluid communication with the chamber andpenetrable by a filling or injection member; a conveyor defining a pathfor transporting the support and the device along the path and throughthe processing space; and within the processing space: ade-contamination station located on the conveyor path and configured tode-contaminate at least the penetrable surface of the penetrable septum;a filling station located on the conveyor path downstream of thede-contamination station and including at least one filling or injectionmember coupled or connectible in fluid communication with a source ofsubstance to be filled into the chamber of the device, wherein at leastone of the filling or injection member and the device is movablerelative to the other within the filling station to penetrate thepenetrable septum with the filling or injection member, introducesubstance through the filling or injection member and into the chamber,and withdraw the filling or injection member from the septum; and aresealing station located on the conveyor path downstream of the fillingstation configured to reseal an aperture formed in the septum during thefilling of the chamber of the device at the filling station; (ii)removing the filling or injection member from the cap and fluidlyconnecting the filling or injection member to a source of substance;(iii) storing the cap of the filling or injection member in the fillingdevice at a storage position; (iv) de-contaminating at least apenetrable surface of a device including a needle penetrable portion orseptum penetrable by a filling or injection member and a sealed chamberin fluid communication with the penetrable septum; (v) moving at leastone of the filling or injection member and the device relative to theother to penetrate the penetrable septum with the filling or injectionmember, introducing substance through the filling or injection memberand into the chamber, and withdrawing the filling or injection memberfrom the septum; and (vi) sealing the penetrated region of the septum.96. A method as defined in claim 95, further comprising the steps of:(vii) retrieving the cap from the storage position; and (viii)re-attaching the cap to the filling or injection member.